Condensed thiophene compound and pharmaceutical use thereof

ABSTRACT

A condensed thiophene compound represented by general formula: ##STR1## or a pharmaceutically acceptable salt thereof, wherein ring S represents a thiophene ring; R 1  represents hydrogen, halogen, alkyl, etc.; R 2  represents hydrogen, alkyl, acyl, etc.; G represents --CH 2  --, --CH(OH)--, --CO--, etc.; Q represents alkylene; T represents --N(Rb)(Rc) (wherein Rb, Rc represents each alkyl etc.; or alternatively Rb and Rc are combined together to form cyclic amino); D represents --CH 2  -- or --S--; A and B represent each carbonyl or thiocarbonyl, or are null; and m and n represent each 0, 1 to 4, provided that m+n represents an integer of 4 or less. 
     This compound is useful as an antipsychotic drug having a reduced extrapyramidal side effect.

This is a divisional of application Ser. No. 08/272,320 filed Jul. 8,1994 now U.S. Pat. No. 5,532,240, which is a continuation-in-part ofprior application Ser. No. 08/107,564 filed Aug. 18, 1993 (abandoned),which is a continuation-in-part of PCT/JP92/0695 filed Dec. 24, 1992.

FIELD OF THE INVENTION

The present invention relates to novel and pharmaceutically usefulcondensed thiophene compounds or salts thereof and pharmaceutical usesthereof, and further synthetic intermediates for said condensedthiophene compounds.

BACKGROUND OF THE INVENTION

The following compounds and the method of preparation thereof aredisclosed in (1) Chemical Abstracts, vol. 55, column 23488 (1961), (2)Nippon Kagaku Zassi, vol: 83-3, pp. 343-347 (1962), Chemical Abstracts,vol. 59, column 3862 (1963)!, (3) Chemical Abstracts, vol. 64, column586 (1966), (4) Chemical Abstracts, vol. 69, 18565x (1968), (5) U.S.Pat. No. 4,735,940, column 39, lines 50-51 and (6) Journal ofHeterocyclic Chemistry, vol. 13, pp. 1347-1349 (1976). ##STR2##

On the other hand, compounds having antipsychotic activity are known bypatent publications such as JP-A S60-84282, JP-A S59-227882, JP-AS58-90583, JP-A S63-132887, JP-A S63-183576, JP-A H1-199967 and JP-AH4-308584.

Antipsychotic drugs introduced in 1950's have been played a large rolein treating schizophrenia.

In 1960's "dopamine hypothesis" concerned with schizophrenia has beensuggested (Carlsson, A. et al, Acta. Pharmacol. Toxicol. 20, 140-144(1963)) and the strong correlation between the affinity of antipsychoticdrugs for D₂ receptors in striatum and the average clinical dose hivebeen reported (Seeman, P. et al, Nature, 261,717-719 (1976), Creese, I.et al, Science, 192,481-483 (1976)). After that, the concept of thedevelopment of anti psychotic drugs was the blockade of D₂ receptors.However, typical antipsychotic drugs are effective for the treatment ofthe positive symptoms such as hallucination and delusions, but noteffective for that of the negative symptoms such as apathy and socialwithdrawal (Zubin, J. et al, Comprehensive Psychiatry, 26, 217-240(1985)). And the extrapyramidal side-effect (EPS: dystonia, akathidia,tardive dyskinesia) and the elevation in the level of serum prolactin inthe acute and chronic treatment of typical antipsychotic drugs are theserious problems for patients.

From these points of view, the development of atypical antipsychoticdrugs, produce fewer EPS and are more effective than typicalantipsychotic drugs in treating schizophrenia, is desired.

The profile of atypical antipsychotic drug are as follows.

1) It is effective for both positive and negative symptoms.

2) It produces fewer EPS.

3) It has no side-effect of internal secretion.

1. Merits by addition of 5-HT₂ receptor antagonistic activity:

In clinical study, it has been reported that the selective 5-HT₂antagonist ritanserin ameliorates negative symptoms and reduces theincidence of EPS caused by typical antipsychotic drug therapy (Bersani,G. et al, Curr. Ther. Res., 10, 492-499 (1986)). And in preclinicalstudy, it has also been reported that 5-HT₂ antagonists reducedcatalepsy induced by haloperidol (Hicks, P. B., Life Sci., 47, 1609-1615(1990)). On the other hand, syndrome malin induced by neuroleptics isthe unbalance of dopaminergic and serotonergic activity in the center ofthe regulation of temperature has been proposed (Yamawaki, N.,Sinkeiseisinyakuri, 11, 17-24 (1989). Therefore, it is expected thatadditional 5-HT₂ receptor antagonism reduces the syndrome malin.

Risperidone has extremely potent 5-HT₂ and potent D₂ receptorantagonistic properties (Janssen, P. A. J. et al, J. Pharmacol. Exp.Ther. 244, 685-693 (1988)), and has revealed a clinical profile that isdistinct from that of existing neuroleptics. Risperidone proved to be aneffective antipsychotic, with low EPS liability and with beneficialeffects on the negative symptoms of schizophrenia (The 1st InternationalRisperidone Investigator's Meeting (Conference Review), Paris (France),Mar. 9-10, 1992), but it has not a character of atypical antipsychoticdrug yet because EPS is appeared in high dose of risperidone and it hasside-effect of internal secretion yet.

2. Merits by addition of 5-HT_(1A) agonist:

5-HT_(1A) agonist has been reported to be possible to make up for thedisadvantage of typical antipsychotic drugs, because 5-HT_(1A) agonistbuspirone improved the depression and EPS caused by haloperidol therapyin clinical study (McMillen, B. A. et al, J. Pharma. Pharmacol., 40,885-887 (1988)). And, it is supported to the above mentioned possibilitythat 5-HT_(1A) agonist 8-OH DPAT and buspirone reverse catalepsy inducedby haloperidol in preclinical study (Golf, D. C. et al, J. Clin.Psychopharmacol. 11, 193-197 (1991)), Invernizzi, R. W. et al,Neuropharmacology, 27, 515-518 (1988)). And then, amplification ofantipsychotic effect by additional 5-HT_(1A) agonistic activity isexpected, because administration of 8-OH DPAT with D₂ antagonist inhibitconditioned avoidance response (CAR) more potent than that of D₂antagonist only (Wadenberg, M. L. et al, J. Neural. Transm. 83, 43-53(1991)).

3. The functional relationships of 5-HT_(1A) receptors and 5-HT₂receptors:

By the study of electrical physiology and biochemistry, it has beenrevealed that 5-HT_(1A) and 5-HT₂ receptors regulate the serotonergicactivity through the K channel (second messenger system in cell)(Bobker, H. H. et al, Trends Neurosci., 13, 169-173 (1990)). Stimulationof 5-HT_(1A) receptor makes a hyperpolarization, and stimulation of5-HT₂ receptor makes a depolarization. Therefore, both 5-HT_(1A) agonistand 5-HT₂ antagonist inhibit the serotonergic activity, and theinhibition of serotonergic activity is amplified if 5-HT_(1A) agonisticand 5-HT₂ antagonistic activities are occurred at the same time. This issupported by the preclinical pharmacological data that anxiolitic andantidepressant effects of 5-HT_(1A) agonist are reinforced by additionof 5-HT₂ antagonist (Millan, M. J. et al, J. Neural. Transm. 83, 43-53(1991)).

As mentioned above, it has been reported that the disadvantages oftypical antipsychotic drugs are improved by addition of 5-HT₂antagonistic and 5-HT_(1A) agonistic activities to the typicalantipsychotic drugs (D₂ antagonists). Especially, negative symptoms mustbe distinguished from depression, but in either symptoms the desiredpharmacological effect is activation, and it is suggested that theaddition of 5-HT_(1A) agonistic activity, that improves the depression,improves the negative symptoms like 5-HT₂ antagonistic activity.

As mentioned above, the amplificational effect of serotonergic activityare expected by addition of both 5-HT_(1A) agonist and 5-HT₂ antagonist,therefore it is expected that the addition of both 5-HT_(1A) agonist and5-HT₂ antagonist to D₂ antagonist is more effective to the negativesymptoms than the addition of either of them to it.

SUMMARY OF THE INVENTION

The present inventors have found that novel condensed thiophenecompounds have D₂, 5-HT₂ antagonistic and 5-HT_(1A) agonistic activitiesand are useful as potent antipsychotic drugs according with theabove-mentioned purposes, and completed the present invention.

DETAILED DESCRIPTION

The present invention provides:

1. a condensed thiophene compound of the formula: ##STR3## or apharmaceutical acceptable salt thereof.

In the above formula, the ring S means following condensed thiophenes.##STR4##

R¹ is hydrogen, halogen, alkyl, acyl or hydroxyalkyl.

R² is hydrogen, alkyl, acyl, carbamoyl, substituted carbamoyl, aryl orarylalkyl.

G is --CH₂ --, --CH(OR³)-- (R³ is hydrogen, alkyl or acyl), --CO--, or--S(O)t- (t is 0, 1 or 2).

Q is straight alkylene or branched chain alkylene.

T is a tertiary amino.

D is --CH₂ -- or --S(O)u- (u is 0, 1 or 2).

A and B are (i) one is absent and the other is carbonyl or thiocarbonyl,or (ii) both absent.

When A, B are the case of above-mentioned (i), m is 0 or 1, and n is 0,1 or 2: When A, B are the case of above-mentioned (ii), m and n are thesame or different and each is 0 or an integer of 1 to 4 with the provisothat m+n is an integer of below 4;

2. the compound of the above-mentioned item 1 or a pharmaceuticallyacceptable salt thereof, wherein T is a tertiary amino of --N(Rb)(Rc),wherein Rb and Rc are the same or different and each is alkyl, or Rb andRc together with the adjacent nitrogen atom form a cyclic amino group ofthe formula: ##STR5## wherein q is an integer of 1 to 4, Z is methylene,or N-R⁵ (R⁵ is aryl, diarylalkyl, heteroaryl or heteroarylalkyl),substituent V is hydrogen, hydroxyl, heteroaryl, heteroarylalkyl orbisarylmethylene and the number of V is 1 to 4. Cyclic amino group offormula (1) may contain carbonyl group in the cycle and further may becondensed with aryl or heteroaryl. Ring Am of formula (2) contain amidobond in the cycle and further may contain oxygen atom, sulfur atom,carbonyl and/or N-R⁶ (R⁶ is hydrogen, alkyl or phenyl).

3. preferable compound of the above-mentioned item 1 selected from thegroup consisting of:

2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H- thieno3,2-b!azepin-5- one,

3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-4,6,7,8-tetrahydro-5H-thieno 3,2-b!azepin-5- one,

2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-8H-thieno 2,3-c!azepin-8-one,

2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydro-8H-thieno 2,3-c!azepin-8- one,

6-acetyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine,

6-acetyl-2-ethyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3 -c!pyridine,

6-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-3-methylthieno2,3-c!pyridine,

6-acetyl-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine,

3-(2-(4-(6-fluoro-3,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methyl-6-propionylthieno 2,3-c!pyridine

6-cyclopropylcarbonyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine,

3,6-diacetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine,

6-acetyl-3-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methyelthieno2,3-c!pyridine,

6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine,

6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno 2,3-c!pyridine, and

6-acetyl-3-ethyl-2-(2-(4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine

or a pharmaceutically acceptable salt thereof;

4. Preferable compound of the above-mentioned item 1 selected from thegroup consisting of:

6-acetyl-3-ethyl-2-(2-(4-(5-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3 -c!pyridine,

2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno 3,2-b!azepin-5-one,

2-(2-(4-(5-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one,

6-acetyl-3-ethyl-2-(2-(4-(5,6-dimethylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine,

3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-5,6,7,8-tetrahydrothieno3,2-c!azepin-4-one,

7-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-8H-thieno2,3-c!azepine,

6-acetyl-3-ethyl-2-(4-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine,

6-acetyl-3-ethyl-2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3 -c!pyridine,

6-acetyl-3-ethyl-2-(2-(4-(7-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno 2,3-c!pyridine,

2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one,

2-(2-(4-(4-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one,

2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno 3,2-b!azepin-5- one,

2-(2-(4-(6-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2 -b!azepin-5- one,

6-acetyl-3-ethyl-2-(2-(4-(5-methylbenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine,

6-acetyl-3-ethyl-2-(2-(4-(6-methylbenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine,

6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine,

6-acetyl-3-ethyl-2-(2-(4-(4-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine,

6-acetyl-3-ethyl-2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyel)-4,5,6,7-tetrahydrothieno2,3- c!pyridine,

6-acetyl-3-ethyl-2-(2-(4-(6-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine,

2-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,6,78-tetrahydro-5H-thieno3,2 -b!azepin-5-one,

2-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-8H-thieno2,3-c!azepin-8-one,

2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-8H-thieno2,3 -c!azepin-8-one,

2-(2-(4-(5-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-8H-thieno2,3-c!azepin-8-one,

2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-8H-thieno 2,3-c!azepin-8-one

or a pharmaceutically acceptable salt thereof;

5. a condensed thiophene compound of the formula: ##STR6## wherein X ishydroxyl, or a reactive atom or group derived from hydroxyl (halogen,methanesulfonyloxy, p-toluenesulfonyloxy and so on), and other symbolsare as defined in the above-mentioned item 1;

6. a pharmaceutical composition comprising a compound of theabove-mentioned item 1 and pharmaceutical additives;

7. an antipsychotic drug containing a compound of the above-mentioneditem 1 as an effective ingredient.

In the definitions of the above symbols and in the presentspecification, halogen means chlorine, bromine, fluorine, iodine; alkylmeans, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, hexyl, heptyl, octyl, decyl, hexadecyl or octadecyl;arylalkyl means, for example, benzyl, 1-phenylethyl, 2-phenylethyl,3-phenylpropyl, 4-phenylbutyl, naphthylmethyl, 2-naphthylethyl,3-naphthylpropyl, 4-naphthylbutyl, diphenylmethyl orbis(4-fluorophenyl)methyl; acyl means, for example, alkanoyl such asformyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl oroctanoyl, aroyl such as benzoyl or naphthoyl, heteroarylcarbonyl such asnicotinyl, thenoyl or furoyl, or cycloalkylcarbonyl such ascyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl orcycloheptylcarbonyl; hydroxyalkyl means, for example, hydroxymethyl, 1-or 2-hydroxyethyl, 1-, 2- or 3-hydroxypropyl or 1-, 2-, 3- or4-hydroxybutyl; aryl means, for example, phenyl or naphthyl; substitutedcarbamoyl means, for example, methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl, cyclohexylcarbamoyl orpiperidinocarbonyl; straight alkylene means, for example, methylene,ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,heptamethylene, octamethylene or decamethylene; branched chain alkylenemeans, for example, alkylene substituted by at least one, preferably 1to 4 alkyl(s) such as propylene, 1-methyltrimethylene,3-methyltrimethylene, 1- methyl-tetramethylene, 4-methyltetramethylene,1,4-dimethyltetramethylene, 6-methylhexamethylene or4,4-dimethyltetramethylene.

In the formula (I), T is a tertiary amino of --N(Rb)(Rc). Wherein Rb andRc are the same or different and each is alkyl (same as the above), and--N(Rb)(Rc) is exemplified by dialkylamino (e.g. dimethylamino,diethylamino, dipropylamino, diisoproylamino, dibutylamino,dihexylamino, dioctylamino), or Rb and Rc together with the adjacentnitrogen atom form a cyclic amino of the formula: ##STR7## wherein q isan integer of 1 to 4, Z is methylene or N-R⁵. Substituent V is hydrogen,hydroxyl, heteroaryl (e.g. pyridyl, thienyl, furyl, pyrimidinyl,1,2-benzoisothiazol-3-yl, 1,2-benzisoxazol-3-yl, benzothiophen-2- or3-yl, benzofuran-2- or 3-yl, quinolyl, isoquinolyl, benzoxazol-2-yl,pyrazinyl, pyridazinyl, imidazolyl, 1H-indazol-3-yl, thieno3,2-c!pyridin-4-yl, furo 3,2-c!pyridin-4-yl, 2-oxo-1-benzimidazolyl,2-thioxo-1,-benzimidazolyl, 2,4-dioxohexahydro-pyrimidin-1-yl,hydantoin-1-yl), heteroarylalkyl (which may optionally be hydrogenatedand is exemplified by pyridylmethyl, furylmethyl, thienylmethyl or(1,4-benzodioxan-2-yl)methyl), or bisarylmethylene (e.g.bis(4-fluorophenyl)methylene, his(4-chlorophenyl)- methylene) and thenumber of V is 1 to 4.

R⁵ of N-R⁵ is aryl (same as the above), diarylalkyl (e.g.diphenylmethyl, bis(4-fluorophenyl)methyl, 2,2-diphenylethyl,2,2-bis(4-fluorophenyl)-ethyl), heteroaryl (same as the above), orheteroarylalkyl (same as the above).

Cyclic amino group of formula (1) may contain carbonyl group in thecycle and further may be fused with aryl (e.g. benzene, naphthalene) orheteroaryl (e.g. furan, thiophene, pyridine, quinoline) to form fusedcyclic amino such as 1,2,3,4-tetrahydroisoquinolin-2-yl or phthalimido.Ring Am of formula (2) contain amido bond in the cycle and further maycontain oxygen atom, sulfur atom, carbonyl and/or N-R⁶ (R⁶ is hydrogen,alkyl or phenyl). The ring Am having amido bond in the cycle includes,for example, thiazolidinone, imidazolidinone, pyrazolidinone orpyrrolidinone.

In the above definitions, the aryl and heteroaryl may optionally besubstituted by 1 to 3 substituents (e.g. halogen, nitro, amino, cyano,haloalkyl, hydroxyl, alkyl, alkoxy or alkenyl) on the aromatic ring.

Preferable embodiments of T are the group represented by the formula:##STR8## wherein R⁷ is 1,2-benzisoxazol-3-yl, 1,2-benzisothiazol-3-yl,benzo(b)furan-3-yl, benzo(b)thiophen-e3-yl,1,1-dioxobenzo(b)thiophen-3-yl or 1H-indazol-3-yl, which may have 1 or 2substituents selected from the group consisting of halogen, C₁₋₄ alkyl(e.g., methyl, ethyl), C₁₋₄ alkoxy (e.g., methoxy, ethoxy), C₂₋₄alkanoyl (e.g., acetyl, propionyl) and 4-fluorophenyl; benzoyl which mayhave 1 to 3 substituents selected from the group consisting of halogen,hydroxy, C₁₋₄ alkyl and C₁₋₄ alkoxy; or bis(4-fluorophenyl)methylene; R⁸is 1,2-bezisoxazol-3-yl, 1,2-benzisothiazol-3-yl, benzo(b)furan-3-yl,benzo(b)thiophen-e3-yl or benzothiazol-2-yl, which may have 1 or 2substituents selected from the group consisting of halogen, C₁₋₄ alkyland C₁₋₄ alkoxy.

More preferable embodiments of T are exemplified by4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl, 4-(5-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl, 4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidin- 1-yl,4-(1,2-benzisothiazol-3-yl)piperidin-1-yl,4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl,4-(6-fluoro-1H-indazol-3-yl)piperidin-1-yl,4-(6-fluoro-1-(4-fluorophenyl)-1H-indazol-3-yl)piperidin-1-yl,4-(1,2-benzisoxazol-3-yl)piperidin-1-yl,4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl,4-(4-fluoro-2-methoxybenzoyl)piperidin-1-yl,4-(2,4-difluorobenzoyl)piperidin-1-yl,4-(2-acetyl-6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl,4-(2-ethyl-6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl,4-(2-methyl-6-fluoro-benzo(b)thiophen-3-yl)piperidin-1-yl,4-(2-ethyl-6-fluorobenzo(b)furan-3-yl)piperidin-1-yl,4-(1,2-benzisoxazol-3-yl)piperazin-1-yl,4-(1,2-benzisothiazol-3-yl)piperazin-1-yl,4-(6-chlorobenzothiazol-2-yl)piperazin-1-yl,4-(6-fluoro-1,1-dioxobenzo(b)thiophen-3-yl)piperidin-1-yl,4-(6-methoxy-1,2-benzisoxazol-3-yl)piperidin-1-yl,4-(5-methylbenzo(b)furan-3-yl)piperidin-1-yl,4-(4,6-dichlorobenzo(b)furan-3-yl)piperidin-1-yl,4-(6-fluoro-2-methylbenzo(b)furan-3-yl)piperidin-1-yl,4-(5-chlorobenzo(b)furan-3-yl)piperidin-1-yl,4-(5-fluorobenzo(b)furan-3-yl)piperidin-1-yl,4-(5-methoxybenzo(b)furan-3-yl)piperidin-1-yl,4-(5-bromobenzo(b)furan-3-yl)piperidin-1-yl,4-(5,6-dimethylbenzo(b)furan-3-yl)piperidin-1-yl,4-(4,6-dimethylbenzo(b)furan-3-yl)piperidin-1-yl,4-(5,7-dimethyl-benzo(b)furan-3-yl)piperidin-1-yl,4-(bis(4-fluorophenyl)methylene)-piperidin-1- yl, 4-(4-hydroxy-2,6-dimethylbenzoyl)piperidin-1-yl,4-(5-chloro-6-methylbenzo(b)furan-3-yl)piperidin-1-yl,4-(6-methyl-benzo(b)furan-3-yl)piperidin-1-yl,4-(5-chloro-2-hydroxybenzoyl)-piperidin-1-yl,4-(7-methylbenzo(b)furan-3-yl)piperidin-1-yl,4-(2-hydroxy-5-methylbenzoyl)piperidin-1-yl,4-(benzo(b)furan-3-yl)piperidin-1-yl, 4-(4-methylbenzo(b)furan-3-yl)piperidin-1-yl, 4-(4-methylbenzo(b)thiophen-e3-yl)piperidin-1-yl,4-(5-methylbenzo(b)thiophen-3-yl)piperidin-1-yl,4-(6-methylbenzo(b)-thiophen-3-yl)piperidin-1-yl,4-(7-methylbenzo(b)thiophen-3-yl)piperidin-1-yl,4-(4-fluorobenzo(b)furan-3-yl)piperazin-1-yl,4-(5-fluorobenzo(b)furan-3-yl)piperazin-1-yl,4-(6-fluorobenzo(b)furan-3-yl)piperazin-1-yl,4-(7-fluorobenzo(b)furan-3-yl)piperazin-1-yl,4-(4-methylbenzo(b)furan-3-yl)piperazin-1-yl,4-(5-methylbenzo(b)furan-3-yl)piperazin-1-yl,4-(6-methylbenzo(b)furan-3-yl)piperazin-1-yl,4-(7-methylbenzo(b)furan-3-yl)piperazin-1-yl,4-(4-fluorobenzo(b)thiophen-3-yl)piperazin-1-yl,4-(5-fluorobenzo(b)thiophen-3-yl)piperazin- 1-yl,4-(6-fluorobenzo(b)thiophen-3-yl)piperazin-1-yl,4-(7-fluorobenzo(b)-thiophen-3-yl)piperazin-1-yl,4-(4-methylbenzo(b)thiophen-3-yl)-piperazin-1-yl,4-(5-methylbenzo(b)thiophen- 3-yl)piperazin- 1-yl,4-(6-methylbenzo(b)-thiophen-3-yl)piperazin-1-yl, 4-(7-methylbenzo(b)-thiophen-3-yl)piperazin-1-yl, and so on.

The salt of the compound of formula (I) include an acid addition saltsuch as hydrochloride, hydrobromide, phosphate, sulfate,benzenesulfonate, methanesulfonate, citrate, lactate, maleate, fumarateor tartarate. When the compound of formula (I) contain carboxyel as asubstituent, the salt includes a metal salt such as sodium salt,potassium salt, calcium salt, aluminum salt, or an amine salt withtriethylamine, or bibasic amino acid salt with lysine etc. Thepharmaceutically acceptable salts thereof are preferable. The presentinvention also includes a hydrate and a solvate of the compound offormula (I).

The compounds of formula (I) or (II) having a chiral carbon atom can beprepared as a racemate or an optically active isomer, and the compoundhaving at least two chiral atoms can be obtained as an individualdiastereomer or a mixture thereof. The present invention embraces themixture thereof and the individual isomers. Furthermore, the presentinvention embraces stereoisomers.

The methods for preparing the compounds of present invention aredescribed as follows:

Method (1)

The compound of formula (I) can be synthesized by reacting the compoundof formula (II) with a compound of the formula:

    H-T                                                        (III)

wherein T is as defined above, or acid addition salt thereof.

The reaction is carried out in an inert solvent such as methanol,ethanol, propanol, benzene, toluene, dimethylformamide, tetrahydrofuran,acetonitrile or acetone in the presence of a suitable acid scavenger(e.g. potassium carbonate, sodium carbonate, sodium hydrogencarbonate,pyridine, triethylamine, sodium acetate or potassium acetate) at 20°C.-150° C. for 30 minutes to e30 hours.

When X in the compound of formula (II) is hydroxyl, the reaction iscarried out in a suitable inert solvent such as dimethylformamide orbenzene in the presence of an aminophosphonium reagent (e.g.N,N-methyl-phenylaminotriphenylphosphonium iodide)at 20° C.-150° C. for30 minutes to 5 hours.

Method (2)

The compound of formula (I) can be synthesized by reacting a compound ofthe formula: ##STR9## wherein each symbol is as defined above, with acompound of the formula:

    X-R.sup.2                                                  (V)

wherein each symbol is as defined above.

The reaction is carried out in an inert solvent such as methanol,ethanol, propanol, N,N-dimethylformamide, benzene, toluene,acetonitrile, diethyl ether, tetrahydrofuran or n-hexane in the presenceof a suitable base such as sodium methoxide, sodium ethoxide, potassiumtert-butoxide, potassium hydride, sodium hydride, sodium hydroxide,potassium hydroxide, sodium carbonate or potassium carbonate at -20C.-150° C. for 30 minutes to 5 hours.

Method (3)

The synthetic intermediate compound of formula (II) wherein G is --CO--can be prepared by reacting a compound of the formula: ##STR10## whereineach symbol is as defined above, with a compound of the formula:

    Z.sup.1 -CO-Q-X                                            (VII)

wherein Z¹ is halogen and other symbols are as defined above.

The reaction is carried out in a suitable and inert solvent such aschloroform, dichloromethane or dichloroethane in the presence of asuitable Lewis acid (e.g. tin chloride, aluminum chloride, ironchloride, zinc chloride) at -10° C. to 100° C. for 30 minutes to 5hours.

Method (4)

The synthetic intermediate compound of formula (II) wherein G is --S--can be prepared by lithiation of the compound of formula (VI) using asuitable alkyl-lithium, followed by reaction with a compound of theformula:

    X.sup.1 -Q-X.sup.2                                         (VIII)

wherein X¹ and X² are the same as the above-mentioned X, but both ofthem are not hydroxyl, in the presence of sulfur.

The reaction is carried out by lithiation using a suitable alkyl-lithiumsuch as butyllithium or sec-butyllithium in a suitable and inert solventsuch as diethyl ether or tetrahydrofuran at a temperature of from -78°C. to the boiling point of the solvent employed, and followed byreaction with sulfur and the compound of formula (VIII).

Method (5)

The synthetic intermediate compound of formula (II) wherein G is --SO--or --SO₂ -- can be prepared by oxidizing the compound synthesized inMethod (4) using a suitable oxidizing agent (e.g. sodium metaperiodate)in a suitable solvent.

Method (6)

The synthetic intermediate compound of formula (II) wherein G is--CH(OH)-- or --CH₂ -- can be prepared by reducing the compound obtainedin Method (3) wherein G is --CO-- using a suitable reducing agent suchas sodium borohydride.

The reaction is carried out in a suitable and inert solvent, forexample, methanol, ethanol, propanol, isoproyl alcohol, tetrahydrofuran,dichloromethane or dichloroethane, in the presence of a suitablereducing agent (e.g. lithium aluminum hydride, sodium borohydride,sodium cyanoborohydride, trifluoroboron diethylate, triethylsilane) at-10° C. to 100° C. for 30 minutes to 10 hours. The compound of formula(I) wherein G is -CH(OH)-- or --CH₂ -- can be prepared by reducing thecompound of formula (I) wherein G is --CO-- in a similar manner as theabove-mentioned method.

Method (7)

The compound of formula (I) wherein G is --CH(OR^(3'))-- (R^(3') isalkyl or acyl) can be prepared by reacting the compound of formula (I)wherein G is --CH(OH)-- with a compound of the formula:

    R.sup.3' -Z.sup.2                                          (IX)

wherein Z² is halogen and R³ is as defined above.

The reaction is carried out in a suitable and inert solvent such asmethanol, ethanol, propanol, butanol, N,N-dimethylformamide,tetrahydrofuran, benzene or toluene in the presence of an acid scavenger(e.g. sodium hydride, sodium amide, sodium methoxide, sodium ethoxide,potassium hydroxide, sodium hydroxide) at room temperature to 150° C.for 1 to 20 hours.

The compound of formula (VI) wherein one of A and B is absent and theother is carbonyl group can be synthesized by, for example, thefollowing methods.

Method (8)

A method which comprises subjecting a compound of the formula: ##STR11##wherein each symbol is as defined above, to Schmidt rearrangement.

The reaction is carried out by reacting the compound of formula (XVIII)with sodium azide in a suitable and inert solvent such as chloroform,methylene chloride, toluene or benzene or without a solvent in thepresence of a suitable acid (e.g. trifluoroacetic acid, polyphosphoricacid, sulfuric acid) at 0° C. to 150° C. for 30 minutes to 10 hours.

Method (9)

A method which comprises subjecting a compound of the formula: ##STR12##wherein R⁵ is hydrogen, alkyl, methanensulfonyl group orp-toluene-sulfonyl group and other symbols are as defined above, toBeckmann rearrangement.

The reaction is carried out by reacting the compound of formula (XIX) ina suitable and inert solvent such as benzene, toluene, dimethylformamideor diethyl ether or without solvent in the presence of a suitable acid(e.g. phosphoric acid, phosphorus oxychloride, phosphorus pentachloride,phosphorus pentoxide, polyphosphoric acid, sulfuric acid) at 0° C. to150° C. for 30 minutes to 10 hours.

The compound of formula (VI) wherein both of A and B are absent can besynthesized by, for example, the following method.

Method (10)

A method which comprises reducing a compound of the formula: ##STR13##wherein each symbol is as defined above.

The reaction is carried out using boron trifluoride-ether complex andsodium borohydride in a suitable and inert solvent such as ether ortetrahydrofuran at 0° C. to the boiling point of the solvent employedfor 30 minutes to 10 hours.

Method (11)

The synthetic intermediate compound of the formula: ##STR14## wherein R¹is as defined above, can be prepared by the following method. ##STR15##The compound of formula (XXII) can be prepared by a dehydrationcondensation of the corresponding aldehyde compound withaminoacetoaldehyde dimethyl acetal. The reaction is carried out in asuitable and inert solvent, for example, tetrahydrofuran, diethyl ether,methylene chloride, benzene or toluene, preferably without solvent at10° C. to 100° C. for 30 minutes to 10 hours.

The compound of formula (XXIII) can be prepared by reducing the compoundof formula (XXII) using a reducing agent such as sodiumcyano-borohydride, lithium aluminum hydride, aluminum hydride ordiisobutylaluminum hydride, preferably sodium borohydride in an inertsolvent such as ethanol, butanol, isopropyl alcohol or tetrahydrofuranat -20° C. to 100° C. for 30 minutes to 15 hours.

The compound of formula (XXIV) can be prepared by reacting the compoundof formula (XXIII) with an acid such as sulfuric acid, p-toluenesulfonicacid or phosphoric acid, prefebrably hydrochloric acid, in an inertsolvent such as water, tetrahydrofuran, diethyl ether or dioxane,preferably in water at 0° C. to 120° C. for 30 minutes to 15 hours.

The compound of formula (XXI) can be prepared by reacting the compoundof formula (XXIV), which usually may not be isolated and purified, witha reducing agent such as a tin(II) chloride in a solvent such as water,tetrahydrofuran, diethyl ether or dioxane, preferably in water, in thepresence of an acid such as sulfuric acid, p-toluenesulfonic acid,phosphoric acid, preferably hydrochloric acid at 0° C. to 120° C. for 30minutes to 15 hours.

The thus obtained compounds of the present invention can be isolated andpurified by a conventional method such as recrystallization or columnchromatography.

When the obtained compound is a racemate, it can be separated intodesired optically active isomers, for example, by means of fractionalrecrystallization of a salt with an optically active acid or columnfilled with an optically active carrier. Individual diastereomers can beseparated by the method such as fractional crystallizatin orchromatography. Such compounds can also be obtained by using anoptically active starting material. Furthermore, the stereoisomers canbe isolated by recrystallization, column chromatography or the like.

The compounds exemplified in the examples and listed in the followingtables, or salts thereof are encompassed in the condensed thiophenecompounds of formula (I) of the present invention. In the tables, "Me"means methyl, "Et" means ethyl, "C₆ H₅ " means phenyl, and the symbols"I" to "X" in "T" means the following amine molecules:

    __________________________________________________________________________     ##STR16##                                                                                        ##STR17##                                                  ##STR18##                                                                                        ##STR19##                                                  ##STR20##                                                                                        ##STR21##                                                  ##STR22##                                                                                        ##STR23##                                                  ##STR24##                                                                                        ##STR25##                                                 No.                                                                              A  B D  m n  R1   R2      G  Q   T                                         __________________________________________________________________________     ##STR26##                                                                    1  -- CO                                                                              CH.sub.2                                                                         0 1  H    H       CO (CH.sub.2).sub.3                                                                  I                                         2  -- CO                                                                              CH.sub.2                                                                         0 1  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         3  -- CO                                                                              CH.sub.2                                                                         0 1  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         4  -- CO                                                                              CH.sub.2                                                                         0 1  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         5  -- CO                                                                              CH.sub.2                                                                         0 1  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         6  -- CO                                                                              CH.sub.2                                                                         0 1  F    H       CO (CH.sub.2).sub.3                                                                  I                                         7  -- CO                                                                              CH.sub.2                                                                         0 1  Cl   H       CO (CH.sub.2).sub.3                                                                  I                                         42 -- CO                                                                              CH.sub.2                                                                         0 1  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         43 -- CO                                                                              CH.sub.2                                                                         0 1  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         44 -- CO                                                                              CH.sub.2                                                                         0 1  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         45 -- CO                                                                              CH.sub.2                                                                         0 1  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         48 -- CO                                                                              CH.sub.2                                                                         0 1  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         47 -- CO                                                                              CH.sub.2                                                                         0 1  F    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         48 -- CO                                                                              CH.sub.2                                                                         0 1  Cl   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         49 -- CO                                                                              CH.sub.2                                                                         0 1  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         83 CO --                                                                              CH.sub.2                                                                         0 1  H    H       CO (CH.sub.2).sub.3                                                                  I                                         84 CO --                                                                              CH.sub.2                                                                         0 1  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         85 CO --                                                                              CH.sub.2                                                                         0 1  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         86 CO --                                                                              CH.sub.2                                                                         0 1  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         87 CO --                                                                              CH.sub.2                                                                         0 1  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         88 CO --                                                                              CH.sub.2                                                                         0 1  F    H       CO (CH.sub.2).sub.3                                                                  I                                         89 CO --                                                                              CH.sub.2                                                                         0 1  Cl   H       CO (CH.sub.2).sub.3                                                                  I                                         90 CO --                                                                              CH.sub.2                                                                         0 1  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         124                                                                              CO --                                                                              CH.sub.2                                                                         0 1  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         125                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         126                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         127                                                                              CO --                                                                              CH.sub.2                                                                         0 1  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         128                                                                              CO --                                                                              CH.sub.2                                                                         0 1  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         129                                                                              CO --                                                                              CH.sub.2                                                                         0 1  F    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         130                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Cl   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         131                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         165                                                                              -- CO                                                                              CH.sub.2                                                                         1 0  H    H       CO (CH.sub.2).sub.3                                                                  I                                         166                                                                              -- CO                                                                              CH.sub.2                                                                         1 0  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         167                                                                              -- CO                                                                              CH.sub.2                                                                         1 0  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         168                                                                              -- CO                                                                              CH.sub.2                                                                         1 0  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         169                                                                              -- CO                                                                              CH.sub.2                                                                         1 0  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         189                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  H    H       CO (CH.sub.2).sub.3                                                                  I                                         190                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         191                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         192                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         193                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         194                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         195                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         196                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         197                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         198                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         199                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         200                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         201                                                                              CO --                                                                              CH.sub.2                                                                         0 2  H    H       CO (CH.sub.2).sub.3                                                                  I                                         202                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         203                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         204                                                                              CO --                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         205                                                                              CO --                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         206                                                                              Co --                                                                              CH.sub.2                                                                         0 2  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         207                                                                              CO --                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         208                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         209                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         210                                                                              CO --                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         211                                                                              CO --                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         212                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         261                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  H    H       CO (CH.sub.2).sub.3                                                                  I                                         262                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         263                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         264                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         265                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         266                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         267                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         268                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         269                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         270                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         271                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         272                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         273                                                                              CO --                                                                              CH.sub.2                                                                         0 3  H    H       CO (CH.sub.2).sub.3                                                                  I                                         274                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         275                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         276                                                                              CO --                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         277                                                                              CO --                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         278                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         279                                                                              CO --                                                                              CH.sub.2                                                                         0 3  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         280                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         281                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         282                                                                              CO --                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         283                                                                              CO --                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         284                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                          ##STR27##                                                                    357                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  H    H       CO (CH.sub.2).sub.3                                                                  I                                         358                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         359                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         360                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         361                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         362                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  F    H       CO (CH.sub.2).sub.3                                                                  I                                         363                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  Cl   H       CO (CH.sub.2).sub.3                                                                  I                                         364                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         397                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  NMe.sub.2                                                                          H       CO (CH.sub.2).sub.3                                                                  I                                         398                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         399                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         400                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         401                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         402                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         403                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  F    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         404                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  Cl   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         405                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         439                                                                              CO --                                                                              CH.sub.2                                                                         0 1  H    H       CO (CH.sub.2).sub.3                                                                  I                                         440                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         441                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         442                                                                              CO --                                                                              CH.sub.2                                                                         0 1  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         443                                                                              CO --                                                                              CH.sub.2                                                                         0 1  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         444                                                                              CO --                                                                              CH.sub.2                                                                         0 1  F    H       CO (CH.sub.2).sub.3                                                                  I                                         445                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Cl   H       CO (CH.sub.2).sub.3                                                                  I                                         446                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         480                                                                              CO --                                                                              CH.sub.2                                                                         0 1  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         481                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         482                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         483                                                                              CO --                                                                              CH.sub.2                                                                         0 1  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         484                                                                              CO --                                                                              CH.sub.2                                                                         0 1  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         485                                                                              CO --                                                                              CH.sub.2                                                                         0 1  F    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         486                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Cl   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         487                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         521                                                                              -- CO                                                                              CH.sub.2                                                                         1 0  H    H       CO (CH.sub.2).sub.3                                                                  I                                         522                                                                              -- CO                                                                              CH.sub.2                                                                         1 0  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         523                                                                              -- CO                                                                              CH.sub.2                                                                         1 0  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         524                                                                              -- CO                                                                              CH.sub.2                                                                         1 0  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         545                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  H    H       CO (CH.sub.2).sub.3                                                                  I                                         546                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         547                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         548                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         549                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         550                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         551                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         552                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         553                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         554                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         555                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         556                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         557                                                                              CO --                                                                              CH.sub.2                                                                         0 2  H    H       CO (CH.sub.2).sub.3                                                                  I                                         558                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         559                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         560                                                                              CO --                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         561                                                                              CO --                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         562                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         563                                                                              CO --                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         564                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         565                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         566                                                                              CO --                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         567                                                                              CO --                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         568                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         617                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  H    H       CO (CH.sub.2).sub.3                                                                  I                                         618                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         619                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         620                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         621                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         622                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         623                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         624                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         625                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         626                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         627                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         628                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         629                                                                              CO --                                                                              CH.sub.2                                                                         0 3  H    H       CO (CH.sub.2).sub.3                                                                  I                                         630                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         631                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         632                                                                              CO --                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         633                                                                              CO --                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         634                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         635                                                                              CO --                                                                              CH.sub.2                                                                         0 3  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         636                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         637                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         638                                                                              CO --                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         639                                                                              CO --                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         640                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                          ##STR28##                                                                    713                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  H    H       CO (CH.sub.2).sub.3                                                                  I                                         714                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         715                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         716                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         717                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         718                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         719                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         720                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         721                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         722                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         723                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         724                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         725                                                                              CO --                                                                              CH.sub.2                                                                         0 1  H    H       CO (CH.sub.2).sub.3                                                                  I                                         726                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         727                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         728                                                                              CO --                                                                              CH.sub.2                                                                         0 1  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         729                                                                              CO --                                                                              CH.sub.2                                                                         0 1  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         730                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         731                                                                              CO --                                                                              CH.sub.2                                                                         0 1  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         732                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         733                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         734                                                                              CO --                                                                              CH.sub.2                                                                         0 1  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         735                                                                              CO --                                                                              CH.sub.2                                                                         0 1  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         736                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         737                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  H    H       CO (CH.sub.2).sub.3                                                                  I                                         738                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         739                                                                              -- CQ                                                                              CH.sub.2                                                                         0 2  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         740                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         741                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         742                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         743                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         744                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         745                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         746                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         747                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         748                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         749                                                                              CO --                                                                              CH.sub.2                                                                         0 2  H    H       CO (CH.sub.2).sub.3                                                                  I                                         750                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         751                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         752                                                                              CO --                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         753                                                                              CO --                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         754                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         755                                                                              CO --                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         758                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         757                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         758                                                                              CO --                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         759                                                                              CO --                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         760                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         761                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  H    H       CO (CH.sub.2).sub.3                                                                  I                                         762                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         763                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         764                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         765                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         766                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         767                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         768                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         769                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         770                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         771                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         772                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         773                                                                              CO --                                                                              CH.sub.2                                                                         0 3  H    H       CO (CH.sub.2).sub.3                                                                  I                                         774                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         775                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         776                                                                              CO --                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         777                                                                              CO --                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         778                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         779                                                                              CO --                                                                              CH.sub.2                                                                         0 3  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         780                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         781                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         782                                                                              CO --                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         783                                                                              CO --                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         784                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                          ##STR29##                                                                    785                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  H    H       CO (CH.sub.2).sub.3                                                                  I                                         786                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         787                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         788                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         789                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         790                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         791                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         792                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         793                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         794                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         795                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         796                                                                              -- CO                                                                              CH.sub.2                                                                         0 1  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         797                                                                              CO --                                                                              CH.sub.2                                                                         0 1  H    H       CO (CH.sub.2).sub.3                                                                  I                                         798                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         799                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         800                                                                              CO --                                                                              CH.sub.2                                                                         0 1  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         801                                                                              CO --                                                                              CH.sub.2                                                                         0 1  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         802                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         803                                                                              CO --                                                                              CH.sub.2                                                                         0 1  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         804                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         805                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         806                                                                              CO --                                                                              CH.sub.2                                                                         0 1  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         807                                                                              CO --                                                                              CH.sub.2                                                                         0 1  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         808                                                                              CO --                                                                              CH.sub.2                                                                         0 1  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         809                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  H    H       CO (CH.sub.2).sub.3                                                                  I                                         810                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         811                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         812                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         813                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         814                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         815                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         816                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         817                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         618                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         819                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         820                                                                              -- CO                                                                              CH.sub.2                                                                         0 2  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         821                                                                              CO --                                                                              CH.sub.2                                                                         0 2  H    H       CO (CH.sub.2).sub.3                                                                  I                                         822                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Me   H       Co (CH.sub.2).sub.3                                                                  I                                         823                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         824                                                                              CO --                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         825                                                                              CO --                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         826                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         827                                                                              CO --                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         828                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         829                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         830                                                                              CO --                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         831                                                                              CO --                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         832                                                                              CO --                                                                              CH.sub.2                                                                         0 2  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         833                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  H    H       CO (CH.sub.2).sub.3                                                                  I                                         834                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         835                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         836                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         837                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         838                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         839                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         840                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         841                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         842                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         843                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         844                                                                              -- CO                                                                              CH.sub.2                                                                         0 3  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         845                                                                              CO --                                                                              CH.sub.2                                                                         0 3  H    H       CO (CH.sub.2).sub.3                                                                  I                                         846                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         847                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Et   H       CO (CH.sub.2).sub.3                                                                  I                                         848                                                                              CO --                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         H       CO (CH.sub.2).sub.3                                                                  I                                         849                                                                              CO --                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  H       CO (CH.sub.2).sub.3                                                                  I                                         850                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Br   H       CO (CH.sub.2).sub.3                                                                  I                                         851                                                                              CO --                                                                              CH.sub.2                                                                         0 3  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         852                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         853                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Et   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         854                                                                              CO --                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         855                                                                              CO --                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         856                                                                              CO --                                                                              CH.sub.2                                                                         0 3  Br   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                          ##STR30##                                                                    857                                                                              -- --                                                                              CH.sub.2                                                                         0 2  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         858                                                                              -- --                                                                              CH.sub.2                                                                         0 2  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         859                                                                              -- --                                                                              CH.sub.2                                                                         0 2  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         860                                                                              -- --                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         861                                                                              -- --                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         862                                                                              -- --                                                                              CH.sub.2                                                                         0 2  H    H       CO (CH.sub.2).sub.3                                                                  I                                         863                                                                              -- --                                                                              CH.sub.2                                                                         0 2  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         864                                                                              -- --                                                                              CH.sub.2                                                                         0 2  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         865                                                                              -- --                                                                              CH.sub.2                                                                         0 2  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         866                                                                              -- --                                                                              CH.sub.2                                                                         0 2  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         867                                                                              -- --                                                                              CH.sub.2                                                                         0 2  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         868                                                                              -- --                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         869                                                                              -- --                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         870                                                                              -- --                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         671                                                                              -- --                                                                              CH.sub.2                                                                         0 2  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         872                                                                              -- --                                                                              CH.sub.2                                                                         0 2  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                         873                                                                              -- --                                                                              CH.sub.2                                                                         1 1  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         874                                                                              -- --                                                                              CH.sub.2                                                                         1 1  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         875                                                                              -- --                                                                              CH.sub.2                                                                         1 1  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         876                                                                              -- --                                                                              CH.sub.2                                                                         1 1  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         877                                                                              -- --                                                                              CH.sub.2                                                                         1 1  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         878                                                                              -- --                                                                              CH.sub.2                                                                         1 1  H    H       CO (CH.sub.2).sub.3                                                                  I                                         879                                                                              -- --                                                                              CH.sub.2                                                                         1 1  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         880                                                                              -- --                                                                              CH.sub.2                                                                         1 1  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         881                                                                              -- --                                                                              CH.sub.2                                                                         1 1  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         882                                                                              -- --                                                                              CH.sub.2                                                                         1 1  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         883                                                                              -- --                                                                              CH.sub.2                                                                         1 1  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         884                                                                              -- --                                                                              CH.sub.2                                                                         1 1  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         885                                                                              -- --                                                                              CH.sub.2                                                                         1 1  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         886                                                                              -- --                                                                              CH.sub.2                                                                         1 1  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         887                                                                              -- --                                                                              CH.sub.2                                                                         1 1  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         888                                                                              -- --                                                                              CH.sub.2                                                                         1 1  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                         889                                                                              -- --                                                                              CH.sub.2                                                                         2 0  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         890                                                                              -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         891                                                                              -- --                                                                              CH.sub.2                                                                         2 0  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         892                                                                              -- --                                                                              CH.sub.2                                                                         2 0  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         893                                                                              -- --                                                                              CH.sub.2                                                                         2 0  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         894                                                                              -- --                                                                              CH.sub.2                                                                         2 0  H    H       CO (CH.sub.2).sub.3                                                                  I                                         895                                                                              -- --                                                                              CH.sub.2                                                                         2 0  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         896                                                                              -- --                                                                              CH.sub.2                                                                         2 0  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         897                                                                              -- --                                                                              CH.sub.2                                                                         2 0  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         898                                                                              -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         899                                                                              -- --                                                                              CH.sub.2                                                                         2 0  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         900                                                                              -- --                                                                              CH.sub.2                                                                         2 0  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         901                                                                              -- --                                                                              CH.sub.2                                                                         2 0  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         902                                                                              -- --                                                                              CH.sub.2                                                                         2 0  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         903                                                                              -- --                                                                              CH.sub.2                                                                         2 0  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         904                                                                              -- --                                                                              CH.sub.2                                                                         2 0  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                          ##STR31##                                                                    905                                                                              -- --                                                                              CH.sub.2                                                                         0 2  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         906                                                                              -- --                                                                              CH.sub.2                                                                         0 2  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         907                                                                              -- --                                                                              CH.sub.2                                                                         0 2  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         908                                                                              -- --                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         909                                                                              -- --                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         910                                                                              -- --                                                                              CH.sub.2                                                                         0 2  H    H       CO (CH.sub.2).sub.3                                                                  I                                         911                                                                              -- --                                                                              CH.sub.2                                                                         0 2  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         912                                                                              -- --                                                                              CH.sub.2                                                                         0 2  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         913                                                                              -- --                                                                              CH.sub.2                                                                         0 2  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         914                                                                              -- --                                                                              CH.sub.2                                                                         0 2  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         915                                                                              -- --                                                                              CH.sub.2                                                                         0 2  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         916                                                                              -- --                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         917                                                                              -- --                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         918                                                                              -- --                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         919                                                                              -- --                                                                              CH.sub.2                                                                         0 2  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         920                                                                              -- --                                                                              CH.sub.2                                                                         0 2  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                         921                                                                              -- --                                                                              CH.sub.2                                                                         1 1  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         922                                                                              -- --                                                                              CH.sub.2                                                                         1 1  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         923                                                                              -- --                                                                              CH.sub.2                                                                         1 1  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         924                                                                              -- --                                                                              CH.sub.2                                                                         1 1  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         925                                                                              -- --                                                                              CH.sub.2                                                                         1 1  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         926                                                                              -- --                                                                              CH.sub.2                                                                         1 1  H    H       CO (CH.sub.2).sub.3                                                                  I                                         927                                                                              -- --                                                                              CH.sub.2                                                                         1 1  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         928                                                                              -- --                                                                              CH.sub.2                                                                         1 1  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         929                                                                              -- --                                                                              CH.sub.2                                                                         1 1  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         930                                                                              -- --                                                                              CH.sub.2                                                                         1 1  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         931                                                                              -- --                                                                              CH.sub.2                                                                         1 1  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         932                                                                              -- --                                                                              CH.sub.2                                                                         1 1  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         933                                                                              -- --                                                                              CH.sub.2                                                                         1 1  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         934                                                                              -- --                                                                              CH.sub.2                                                                         1 1  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         935                                                                              -- --                                                                              CH.sub.2                                                                         1 1  H    He      CH.sub.2                                                                         CH.sub.2                                                                          I                                         936                                                                              -- --                                                                              CH.sub.2                                                                         1 1  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                         937                                                                              -- --                                                                              CH.sub.2                                                                         2 0  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         938                                                                              -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         939                                                                              -- --                                                                              CH.sub.2                                                                         2 0  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         940                                                                              -- --                                                                              CH.sub.2                                                                         2 0  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         941                                                                              -- --                                                                              CH.sub.2                                                                         2 0  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         942                                                                              -- --                                                                              CH.sub.2                                                                         2 0  H    H       CO (CH.sub.2).sub.3                                                                  I                                         943                                                                              -- --                                                                              CH.sub.2                                                                         2 0  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         944                                                                              -- --                                                                              CH.sub.2                                                                         2 0  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         945                                                                              -- --                                                                              CH.sub.2                                                                         2 0  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         946                                                                              -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         947                                                                              -- --                                                                              CH.sub.2                                                                         2 0  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         948                                                                              -- --                                                                              CH.sub.2                                                                         2 0  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         949                                                                              -- --                                                                              CH.sub.2                                                                         2 0  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         950                                                                              -- --                                                                              CH.sub.2                                                                         2 0  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         951                                                                              -- --                                                                              CH.sub.2                                                                         2 0  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         952                                                                              -- --                                                                              CH.sub.2                                                                         2 0  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                          ##STR32##                                                                    953                                                                              -- --                                                                              CH.sub.2                                                                         0 3  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         954                                                                              -- --                                                                              CH.sub.2                                                                         0 3  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         955                                                                              -- --                                                                              CH.sub.2                                                                         0 3  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         956                                                                              -- --                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         957                                                                              -- --                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         958                                                                              -- --                                                                              CH.sub.2                                                                         0 3  H    H       CO (CH.sub.2).sub.3                                                                  I                                         959                                                                              -- --                                                                              CH.sub.2                                                                         0 3  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         960                                                                              -- --                                                                              CH.sub.2                                                                         0 3  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         961                                                                              -- --                                                                              CH.sub.2                                                                         0 3  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         962                                                                              -- --                                                                              CH.sub.2                                                                         0 3  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         963                                                                              -- --                                                                              CH.sub.2                                                                         0 3  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         964                                                                              -- --                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         965                                                                              -- --                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         966                                                                              -- --                                                                              CH.sub.2                                                                         0 3  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         967                                                                              -- --                                                                              CH.sub.2                                                                         0 3  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         968                                                                              -- --                                                                              CH.sub.2                                                                         0 3  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                         969                                                                              -- --                                                                              CH.sub.2                                                                         1 2  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         970                                                                              -- --                                                                              CH.sub.2                                                                         1 2  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         971                                                                              -- --                                                                              CH.sub.2                                                                         1 2  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         972                                                                              -- --                                                                              CH.sub.2                                                                         1 2  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         973                                                                              -- --                                                                              CH.sub.2                                                                         1 2  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         974                                                                              -- --                                                                              CH.sub.2                                                                         1 2  H    H       CO (CH.sub.2).sub.3                                                                  I                                         975                                                                              -- --                                                                              CH.sub.2                                                                         1 2  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         976                                                                              -- --                                                                              CH.sub.2                                                                         1 2  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         977                                                                              -- --                                                                              CH.sub.2                                                                         1 2  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         978                                                                              -- --                                                                              CH.sub.2                                                                         1 2  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         979                                                                              -- --                                                                              CH.sub.2                                                                         1 2  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         980                                                                              -- --                                                                              CH.sub.2                                                                         1 2  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         981                                                                              -- --                                                                              CH.sub.2                                                                         1 2  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         982                                                                              -- --                                                                              CH.sub.2                                                                         1 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         983                                                                              -- --                                                                              CH.sub.2                                                                         1 2  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         984                                                                              -- --                                                                              CH.sub.2                                                                         1 2  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                         1001                                                                             -- --                                                                              CH.sub.2                                                                         3 0  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1002                                                                             -- --                                                                              CH.sub.2                                                                         3 0  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1003                                                                             -- --                                                                              CH.sub.2                                                                         3 0  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1004                                                                             -- --                                                                              CH.sub.2                                                                         3 0  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1005                                                                             -- --                                                                              CH.sub.2                                                                         3 0  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1006                                                                             -- --                                                                              CH.sub.2                                                                         3 0  H    H       CO (CH.sub.2).sub.3                                                                  I                                         1007                                                                             -- --                                                                              CH.sub.2                                                                         3 0  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         1008                                                                             -- --                                                                              CH.sub.2                                                                         3 0  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         1009                                                                             -- --                                                                              CH.sub.2                                                                         3 0  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1010                                                                             -- --                                                                              CH.sub.2                                                                         3 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1011                                                                             -- --                                                                              CH.sub.2                                                                         3 0  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1012                                                                             -- --                                                                              CH.sub.2                                                                         3 0  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1013                                                                             -- --                                                                              CH.sub.2                                                                         3 0  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1014                                                                             -- --                                                                              CH.sub.2                                                                         3 0  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         1015                                                                             -- --                                                                              CH.sub.2                                                                         3 0  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         1016                                                                             -- --                                                                              CH.sub.2                                                                         3 0  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                          ##STR33##                                                                    1017                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1018                                                                             -- --                                                                              CH.sub.2                                                                         0 3  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1019                                                                             -- --                                                                              CH.sub.2                                                                         0 3  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1020                                                                             -- --                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1021                                                                             -- --                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1022                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    H       CO (CH.sub.2).sub.3                                                                  I                                         1023                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         1024                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         1025                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1026                                                                             -- --                                                                              CH.sub.2                                                                         0 3  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1027                                                                             -- --                                                                              CH.sub.2                                                                         0 3  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1028                                                                             -- --                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1029                                                                             -- --                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1030                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         1031                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         1032                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                         1033                                                                             -- --                                                                              CH.sub.2                                                                         1 2  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1034                                                                             -- --                                                                              CH.sub.2                                                                         1 2  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1035                                                                             -- --                                                                              CH.sub.2                                                                         1 2  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1036                                                                             -- --                                                                              CH.sub.2                                                                         1 2  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1037                                                                             -- --                                                                              CH.sub.2                                                                         1 2  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1038                                                                             -- --                                                                              CH.sub.2                                                                         1 2  H    H       CO (CH.sub.2).sub.3                                                                  I                                         1039                                                                             -- --                                                                              CH.sub.2                                                                         1 2  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         1040                                                                             -- --                                                                              CH.sub.2                                                                         1 2  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         1041                                                                             -- --                                                                              CH.sub.2                                                                         1 2  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1042                                                                             -- --                                                                              CH.sub.2                                                                         1 2  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1043                                                                             -- --                                                                              CH.sub.2                                                                         1 2  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1044                                                                             -- --                                                                              CH.sub.2                                                                         1 2  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1045                                                                             -- --                                                                              CH.sub.2                                                                         1 2  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1046                                                                             -- --                                                                              CH.sub.2                                                                         1 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         1047                                                                             -- --                                                                              CH.sub.2                                                                         1 2  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         1048                                                                             -- --                                                                              CH.sub.2                                                                         1 2  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                         1065                                                                             -- --                                                                              CH.sub.2                                                                         3 0  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1066                                                                             -- --                                                                              CH.sub.2                                                                         3 0  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1067                                                                             -- --                                                                              CH.sub.2                                                                         3 0  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1068                                                                             -- --                                                                              CH.sub.2                                                                         3 0  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1069                                                                             -- --                                                                              CH.sub.2                                                                         3 0  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1070                                                                             -- --                                                                              CH.sub.2                                                                         3 0  H    H       CO (CH.sub.2).sub.3                                                                  I                                         1071                                                                             -- --                                                                              CH.sub.2                                                                         3 0  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         1072                                                                             -- --                                                                              CH.sub.2                                                                         3 0  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         1073                                                                             -- --                                                                              CH.sub.2                                                                         3 0  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1074                                                                             -- --                                                                              CH.sub.2                                                                         3 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1075                                                                             -- --                                                                              CH.sub.2                                                                         3 0  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1076                                                                             -- --                                                                              CH.sub.2                                                                         3 0  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1077                                                                             -- --                                                                              CH.sub.2                                                                         3 0  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1078                                                                             -- --                                                                              CH.sub.2                                                                         3 0  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         1079                                                                             -- --                                                                              CH.sub.2                                                                         3 0  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         1080                                                                             -- --                                                                              CH.sub.2                                                                         3 0  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                          ##STR34##                                                                    1081                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1082                                                                             -- --                                                                              CH.sub.2                                                                         0 4  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1083                                                                             -- --                                                                              CH.sub.2                                                                         0 4  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1084                                                                             -- --                                                                              CH.sub.2                                                                         0 4  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1085                                                                             -- --                                                                              CH.sub.2                                                                         0 4  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1086                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    H       CO (CH.sub.2).sub.3                                                                  I                                         1087                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         1088                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         1089                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1090                                                                             -- --                                                                              CH.sub.2                                                                         0 4  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1091                                                                             -- --                                                                              CH.sub.2                                                                         0 4  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1092                                                                             -- --                                                                              CH.sub.2                                                                         0 4  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1093                                                                             -- --                                                                              CH.sub.2                                                                         0 4  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1094                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         1095                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         1096                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                         1097                                                                             -- --                                                                              CH.sub.2                                                                         1 3  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1098                                                                             -- --                                                                              CH.sub.2                                                                         1 3  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1099                                                                             -- --                                                                              CH.sub.2                                                                         1 3  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1100                                                                             -- --                                                                              CH.sub.2                                                                         1 3  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1101                                                                             -- --                                                                              CH.sub.2                                                                         1 3  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1102                                                                             -- --                                                                              CH.sub.2                                                                         1 3  H    H       CO (CH.sub.2).sub.3                                                                  I                                         1103                                                                             -- --                                                                              CH.sub.2                                                                         1 3  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         1104                                                                             -- --                                                                              CH.sub.2                                                                         1 3  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         1105                                                                             -- --                                                                              CH.sub.2                                                                         1 3  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1106                                                                             -- --                                                                              CH.sub.2                                                                         1 3  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1107                                                                             -- --                                                                              CH.sub.2                                                                         1 3  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1108                                                                             -- --                                                                              CH.sub.2                                                                         1 3  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1109                                                                             -- --                                                                              CH.sub.2                                                                         1 3  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1110                                                                             -- --                                                                              CH.sub.2                                                                         1 3  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         1111                                                                             -- --                                                                              CH.sub.2                                                                         1 3  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         1112                                                                             -- --                                                                              CH.sub.2                                                                         1 3  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                         1145                                                                             -- --                                                                              CH.sub.2                                                                         4 0  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1146                                                                             -- --                                                                              CH.sub.2                                                                         4 0  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1147                                                                             -- --                                                                              CH.sub.2                                                                         4 0  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1148                                                                             -- --                                                                              CH.sub.2                                                                         4 0  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1149                                                                             -- --                                                                              CH.sub.2                                                                         4 0  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1150                                                                             -- --                                                                              CH.sub.2                                                                         4 0  H    H       CO (CH.sub.2).sub.3                                                                  I                                         1151                                                                             -- --                                                                              CH.sub.2                                                                         4 0  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         1152                                                                             -- --                                                                              CH.sub.2                                                                         4 0  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         1153                                                                             -- --                                                                              CH.sub.2                                                                         4 0  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1154                                                                             -- --                                                                              CH.sub.2                                                                         4 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1155                                                                             -- --                                                                              CH.sub.2                                                                         4 0  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1156                                                                             -- --                                                                              CH.sub.2                                                                         4 0  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1157                                                                             -- --                                                                              CH.sub.2                                                                         4 0  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1158                                                                             -- --                                                                              CH.sub.2                                                                         4 0  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         1159                                                                             -- --                                                                              CH.sub.2                                                                         4 0  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         1160                                                                             -- --                                                                              CH.sub.2                                                                         4 0  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                          ##STR35##                                                                    1161                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1162                                                                             -- --                                                                              CH.sub.2                                                                         0 4  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1163                                                                             -- --                                                                              CH.sub.2                                                                         0 4  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1164                                                                             -- --                                                                              CH.sub.2                                                                         0 4  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1165                                                                             -- --                                                                              CH.sub.2                                                                         0 4  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1166                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    H       CO (CH.sub.2).sub.3                                                                  I                                         1167                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         1168                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         1169                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1170                                                                             -- --                                                                              CH.sub.2                                                                         0 4  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1171                                                                             -- --                                                                              CH.sub.2                                                                         0 4  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1172                                                                             -- --                                                                              CH.sub.2                                                                         0 4  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1173                                                                             -- --                                                                              CH.sub.2                                                                         0 4  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1174                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         1175                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         1176                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                         1177                                                                             -- --                                                                              CH.sub.2                                                                         1 3  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1178                                                                             -- --                                                                              CH.sub.2                                                                         1 3  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1179                                                                             -- --                                                                              CH.sub.2                                                                         1 3  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1180                                                                             -- --                                                                              CH.sub.2                                                                         1 3  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1181                                                                             -- --                                                                              CH.sub.2                                                                         1 3  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1182                                                                             -- --                                                                              CH.sub.2                                                                         1 3  H    H       CO (CH.sub.2).sub.3                                                                  I                                         1183                                                                             -- --                                                                              CH.sub.2                                                                         1 3  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         1184                                                                             -- --                                                                              CH.sub.2                                                                         1 3  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         1185                                                                             -- --                                                                              CH.sub.2                                                                         1 3  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1186                                                                             -- --                                                                              CH.sub.2                                                                         1 3  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1187                                                                             -- --                                                                              CH.sub.2                                                                         1 3  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1188                                                                             -- --                                                                              CH.sub.2                                                                         1 3  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1189                                                                             -- --                                                                              CH.sub.2                                                                         1 3  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1190                                                                             -- --                                                                              CH.sub.2                                                                         1 3  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         1191                                                                             -- --                                                                              CH.sub.2                                                                         1 3  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         1192                                                                             -- --                                                                              CH.sub.2                                                                         1 3  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                         1225                                                                             -- --                                                                              CH.sub.2                                                                         4 0  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1226                                                                             -- --                                                                              CH.sub.2                                                                         4 0  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1227                                                                             -- --                                                                              CH.sub.2                                                                         4 0  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1228                                                                             -- --                                                                              CH.sub.2                                                                         4 0  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1229                                                                             -- --                                                                              CH.sub.2                                                                         4 0  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1230                                                                             -- --                                                                              CH.sub.2                                                                         4 0  H    H       CO (CH.sub.2).sub.3                                                                  I                                         1231                                                                             -- --                                                                              CH.sub.2                                                                         4 0  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         1232                                                                             -- --                                                                              CH.sub.2                                                                         4 0  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         1233                                                                             -- --                                                                              CH.sub.2                                                                         4 0  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1234                                                                             -- --                                                                              CH.sub.2                                                                         4 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1235                                                                             -- --                                                                              CH.sub.2                                                                         4 0  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1236                                                                             -- --                                                                              CH.sub.2                                                                         4 0  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1237                                                                             -- --                                                                              CH.sub.2                                                                         4 0  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1238                                                                             -- --                                                                              CH.sub.2                                                                         4 0  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         1239                                                                             -- --                                                                              CH.sub.2                                                                         4 0  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         1240                                                                             -- --                                                                              CH.sub.2                                                                         4 0  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                          ##STR36##                                                                    1241                                                                             -- --                                                                              CH.sub.2                                                                         0 2  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1242                                                                             -- --                                                                              CH.sub.2                                                                         0 2  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1243                                                                             -- --                                                                              CH.sub.2                                                                         0 2  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1244                                                                             -- --                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1245                                                                             -- --                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1246                                                                             -- --                                                                              CH.sub.2                                                                         0 2  H    H       CO (CH.sub.2).sub.3                                                                  I                                         1247                                                                             -- --                                                                              CH.sub.2                                                                         0 2  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         1248                                                                             -- --                                                                              CH.sub.2                                                                         0 2  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         1249                                                                             -- --                                                                              CH.sub.2                                                                         0 2  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1250                                                                             -- --                                                                              CH.sub.2                                                                         0 2  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1251                                                                             -- --                                                                              CH.sub.2                                                                         0 2  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1252                                                                             -- --                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1253                                                                             -- --                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1254                                                                             -- --                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         1255                                                                             -- --                                                                              CH.sub.2                                                                         0 2  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         1256                                                                             -- --                                                                              CH.sub.2                                                                         0 2  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                         1257                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1258                                                                             -- --                                                                              CH.sub.2                                                                         0 3  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1259                                                                             -- --                                                                              CH.sub.2                                                                         0 3  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1260                                                                             -- --                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1261                                                                             -- --                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1262                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    H       CO (CH.sub.2).sub.3                                                                  I                                         1263                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         1264                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         1265                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1266                                                                             -- --                                                                              CH.sub.2                                                                         0 3  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1267                                                                             -- --                                                                              CH.sub.2                                                                         0 3  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1268                                                                             -- --                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1269                                                                             -- --                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1270                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         1271                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         1272                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                          ##STR37##                                                                    1289                                                                             -- --                                                                              CH.sub.2                                                                         0 2  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1290                                                                             -- --                                                                              CH.sub.2                                                                         0 2  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1291                                                                             -- --                                                                              CH.sub.2                                                                         0 2  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1292                                                                             -- --                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1293                                                                             -- --                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1294                                                                             -- --                                                                              CH.sub.2                                                                         0 2  H    H       CO (CH.sub.2).sub.3                                                                  I                                         1295                                                                             -- --                                                                              CH.sub.2                                                                         0 2  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         1296                                                                             -- --                                                                              CH.sub.2                                                                         0 2  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         1297                                                                             -- --                                                                              CH.sub.2                                                                         0 2  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1298                                                                             -- --                                                                              CH.sub.2                                                                         0 2  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1299                                                                             -- --                                                                              CH.sub.2                                                                         0 2  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1300                                                                             -- --                                                                              CH.sub.2                                                                         0 2  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1301                                                                             -- --                                                                              CH.sub.2                                                                         0 2  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1302                                                                             -- --                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         1303                                                                             -- --                                                                              CH.sub.2                                                                         0 2  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         1304                                                                             -- --                                                                              CH.sub.2                                                                         0 2  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                         1305                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1306                                                                             -- --                                                                              CH.sub.2                                                                         0 3  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1307                                                                             -- --                                                                              CH.sub.2                                                                         0 3  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1309                                                                             -- --                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1310                                                                             -- --                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1311                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    H       CO (CH.sub.2).sub.3                                                                  I                                         1312                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         1313                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         1314                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1315                                                                             -- --                                                                              CH.sub.2                                                                         0 3  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1316                                                                             -- --                                                                              CH.sub.2                                                                         0 3  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1317                                                                             -- --                                                                              CH.sub.2                                                                         0 3  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1318                                                                             -- --                                                                              CH.sub.2                                                                         0 3  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1319                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         1320                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         1321                                                                             -- --                                                                              CH.sub.2                                                                         0 3  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                         1322                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1323                                                                             -- --                                                                              CH.sub.2                                                                         0 4  Me   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1324                                                                             -- --                                                                              CH.sub.2                                                                         0 4  Et   CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1325                                                                             -- --                                                                              CH.sub.2                                                                         0 4  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1326                                                                             -- --                                                                              CH.sub.2                                                                         0 4  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CO (CH.sub.2).sub.3                                                                  I                                         1327                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    H       CO (CH.sub.2).sub.3                                                                  I                                         1328                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    Me      CO (CH.sub.2).sub.3                                                                  I                                         1329                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    C.sub.6 H.sub.5 CO                                                                    CO (CH.sub.2).sub.3                                                                  I                                         1330                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1331                                                                             -- --                                                                              CH.sub.2                                                                         0 4  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1332                                                                             -- --                                                                              CH.sub.2                                                                         0 4  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1333                                                                             -- --                                                                              CH.sub.2                                                                         0 4  COCH.sub.3                                                                         CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1334                                                                             -- --                                                                              CH.sub.2                                                                         0 4  COC.sub.6 H.sub.5                                                                  CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          I                                         1335                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         1336                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                         1337                                                                             -- --                                                                              CH.sub.2                                                                         0 4  H    C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                          ##STR38##                                                                    1338                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          II                                        1339                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          III                                       1340                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          IV                                        1341                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          V                                         1342                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          VI                                        1343                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          VII                                       1344                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          VIII                                      1345                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          IX                                        1346                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          X                                          ##STR39##                                                                    1348                                                                             -- CO                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          II                                        1349                                                                             -- CO                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          III                                       1350                                                                             -- CO                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          IV                                        1351                                                                             -- CO                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          V                                         1352                                                                             -- CO                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          VI                                        1353                                                                             -- CO                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          VII                                       1354                                                                             -- CO                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          VIII                                      1355                                                                             -- CO                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          IX                                        1356                                                                             -- CO                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          X                                          ##STR40##                                                                    1358                                                                             -- CO                                                                              CH.sub.2                                                                         0 2  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          II                                        1359                                                                             -- CO                                                                              CH.sub.2                                                                         0 2  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          III                                       1360                                                                             -- CO                                                                              CH.sub.2                                                                         0 2  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          IV                                        1361                                                                             -- CO                                                                              CH.sub.2                                                                         0 2  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          V                                         1352                                                                             -- CO                                                                              CH.sub.2                                                                         0 2  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          VI                                        1363                                                                             -- CO                                                                              CH.sub.2                                                                         0 2  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          VII                                       1364                                                                             -- CO                                                                              CH.sub.2                                                                         0 2  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          VIII                                      1365                                                                             -- CO                                                                              CH.sub.2                                                                         0 2  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          IX                                        1366                                                                             -- CO                                                                              CH.sub.2                                                                         0 2  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          X                                          ##STR41##                                                                    1368                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          II                                        1369                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          III                                       1370                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          IV                                        1371                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          V                                         1372                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          VI                                        1373                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          VII                                       1374                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          VIII                                      1375                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          IX                                        1376                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          X                                         1378                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   CH.sub.3 CH.sub.2 CO                                                                  CH.sub.2                                                                         CH.sub.2                                                                          I                                         1379                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   (CH.sub.3).sub.2 CHCO                                                                 CH.sub.2                                                                         CH.sub.2                                                                          I                                         1380                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   Cyclopropyl-CO                                                                        CH.sub.2                                                                         CH.sub.2                                                                          I                                         1381                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   C.sub.6 H.sub.5 CO                                                                    CH.sub.2                                                                         CH.sub.2                                                                          I                                         1382                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   Cyclohexyl-CO                                                                         CH.sub.2                                                                         CH.sub.2                                                                          I                                         1383                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         1384                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Me   Me      CH.sub.2                                                                         CH.sub.2                                                                          I                                          ##STR42##                                                                    1385                                                                             -- --                                                                              CH.sub.2                                                                         0 2  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         1386                                                                             -- --                                                                              CH.sub.2                                                                         0 2  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         1387                                                                             -- --                                                                              CH.sub.2                                                                         1 1  Me   H       CH.sub.2                                                                         CH.sub.2                                                                          I                                         1388                                                                             -- --                                                                              CH.sub.2                                                                         1 1  Me   H       CO (CH.sub.2).sub.3                                                                  I                                         1389                                                                             -- --                                                                              CH.sub.2                                                                         2 0  Et   CH.sub.3 CO                                                                           CH.sub.2                                                                         CH.sub.2                                                                          V                                          ##STR43##                                                                    1390                                                                             -- --                                                                              CH.sub.2                                                                         2 0  H    COCH.sub.3                                                                            CO (CH.sub.2).sub.3                                                                  V                                         1391                                                                             -- CO                                                                              CH.sub.2                                                                         0 2  H    H       CH.sub.2                                                                         CH.sub.2                                                                          V                                         __________________________________________________________________________

The pharmacological activities of the compound of formula (I) wereexamined by a series of receptor binding tests, anti-apomorphine actionand anti-ergometrine action as described below.

Experiment Example 1: Affinity for dopamine 2 receptor

A specific binding of dopamine 2 (D₂) receptor was tested according tothe method described in Eur. J. Pharmacol. 46, 377 (1977).

A synaptosome fraction was separated from corpus striatum of 9-10week-old Wistar rats, and suspended in 50 mM Tris-HCl buffer (pH 7.1)containing 120 mM sodium chloride, 5 mM potassium chloride, 2 mM calciumchloride, 1 mM magnesium chloride, 10 μM pargyline and 0.1% ascorbicacid for the experiment.

The test compound at several concentrations and tritiated spiperone(final concentration 0.2 nM) were added to the synaptosome suspension,and each mixture was incubated at 37° C. for 20 minutes. After theincubation, the mixture was filtered with suction through Whatman GF/B(trade mark) glass filter. The filter was washed with 50 mM Tris-HClbuffer (pH 7.7), and the radioactivity of the filter was measured by aliquid scintillation counter. Non-specific binding was determined in thepresence of 10⁻⁴ M (±)-sulpiride. The concentration necessary for 50%inhibition (IC₅₀) was determined on a graph, and inhibition constant (Kivalue) was calculated. The results are shown in Table 1.

Experiment Example 2: Affinity for serotonin 2 receptor

A specific binding of serotonin 2 (5-H₂) receptor was tested accordingto the method described in Mol. Pharmacol. 21, 301 (1981).

A crude synaptosome fraction was separated from hippocampus of 9-10week-old Wistar rats, and suspended in 50 mM Tris-HCl buffer (pH 7.7)for the experiment. The test compound at several concentration andtritiated ketanserin (final concentration 0.2 nM) were added to thesynaptosome suspension, and each mixture was incubated at 37° C. for 20minutes. After the incubation, the mixture was filtered with suctionthrough Whatman GF/B (trade mark) glass filter. The filter was washedwith 50 mM Tris-HCl buffer (pH 7.7), and the radioactivity of the filterwas measured by a liquid scintillation counter. Non-specific binding wasdetermined in the presence of 10⁻⁵ M mianserin. The concentrationnecessary for 50% inhibition (IC₅₀) was determined on a graph, andinhibition constant (Ki value ) was calculated. The result are shown inTable 1.

Experiment Example 3: Affinity for serotonin 1A receptor

A specific binding of serotonin 1A (5-HT_(1A)) receptor was testedaccording to the method described in J. Neurochem. 44, 1685 (1985).

A crude synaptosome fraction was separated from hippocampus of 9-10week-old Wistar rats, and suspended in 50 mM Tris-HCl buffer (pH 7.4)containing 1 mM manganese chloride for the experiment. The test compoundat several concentrations and tritiated8-hydroxy-2-dipropyl-aminotetralin (8-OH-DPAT, final concentration 0.2nM) were added to the synaptosome suspension, and each mixture wasincubated at 37° C. for 12 minutes. After the incubation, the mixturewas filtered with suction through Whatman GF/B (trade mark) glassfilter. The filter was washed with 50 mM Tris-HCl buffer (pH 7.7), andthe radioactivity of the filter was measured by a liquid scintillationcounter. Non-specific binding was determined in the presence of 10⁻⁵ Mserotonin (5-HT). The concentration necessary for 50% inhibition (IC₅₀)was determined on a graph, and inhibition constant (Ki value) wascalculated. The results are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                        Test compound                                                                            Ki (nM)                                                            (Example No.)                                                                            D.sub.2     5-HT.sub.2                                                                            5-HT.sub.14                                    ______________________________________                                        15         0.065       0.32    1.6                                            22         0.52        0.21    15                                             24         0.46        0.062   32                                             32         0.10        0.086   54                                             42         0.23        0.20    1.1                                            43         1.5         0.11    87                                             53         0.15        0.043   3.7                                            73         0.25        0.082   0.16                                           84         0.21        0.18    0.13                                           85         0.52        0.38    0.31                                           86         0.17        0.092   0.59                                           145        3.8         2.8     0.14                                           147        0.4         0.86    0.32                                           148        2.3         8.6     0.24                                           ______________________________________                                    

Experiment Example 4: Anti-apomorphine action (in mouse)

Male dd mice at 3 per group were used for the experiment. The testcompound was orally administered to the mice, and 60 minutes later, 0.5mg/kg of apomorphine hydrochloride was subcutaneously administered.

the movement for 20 minutes from immediately after the administration ofapomorphine hydrochloride was measured using Valimex (Columbus, USA).Each group was tested four times, and the amount of the test compoundnecessary to lower the movement by 50% than that of a control group wascalculated from a graph and taken as ED₅₀. The results are shown inTable 2.

Experiment Example 5: Anti-ergometrine action

Male ddY mice at 12 per group were used for the experiment. The testcompound was orally administered to the mice, and 60 minutes later, 20mg/kg of ergometrine maleate was intraperitoneally administered. Theamount of the test compound necessary to vanish the head-twitch reactionfor 10 minutes from immediately after the administration of ergometrinemaleate was calculated as ED₅₀ value by Probit method. The results areshown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Test compound                                                                              ED.sub.50 (mg/kg, p.o.)                                          (Example No.)                                                                              anti-apomorphine                                                                          anti-ergometrine                                     ______________________________________                                        15           0.063       0.089                                                22           1.1         1.5                                                  24           0.39        0.37                                                 42           0.20        0.19                                                 73           0.25        0.35                                                 84           0.73        0.95                                                 85           0.79        0.52                                                 86           0.54        0.27                                                 ______________________________________                                    

Experimental Example 6: Catalepsy Test

The method of Simon, P. et al (J. Pharm. Pharmacol., 22, 546, 1970) wasutilized with a slight modification.

Catalepsy in rats was evaluated at the various time after oraladministration of test drugs using a horizontal bar positioned 7 cmabove the bench. Cataleptogenic activity was judged to be positive whenthe forepaws of the rats remained on the bar for more than 30 sec. Tenrats at each dose level were used to determine the ED₅₀ value requiredto induce catalepsy in 50% of the animals.

Experiment Example 7: Acute toxicity

Male ddY mice weighing 20-28 g were used at 10 per group. They wereorally administered with the compound of Example 24 and observed for 5days after the administration. The LD₅₀ (50% lethal dose) was 205 mg/kg.

The compounds of formula (I) were found to have high affinities fordopamine (D₂) receptor and serotonin (5-HT_(1A), 5-HT₂) receptorsaccording to the receptor binding assay using the radioligands. And theypossessed D₂ antagonistic, 5-HT₂ antagonistic and 5-HT_(1A) agonisticactivities according to the inhibition of apomorphine-inducedhyperactivity, ergometrine-induced head-twitches and forskolin-inducedadenylate cyclase activity, respectively. Further they were found tohave the inhibitory activity of spontaneous locomotor activity,methanphetamine-induced hyperactivity and conditioned avoidanceresponding. Therefore, these compounds will be effective for thepositive symptoms such as hallucination and dellusion. And they werefound to be effective for the forced swimming test, an indication ofactivation, and to have low cataleptogenic activity, an indication ofthe extrapyramidal side-effects. Therefore, these compounds will also beeffective for the negative symptoms, such as apathy and socialwithdrawal. And they will be effective antipsychotic drugs with thepotential for fewer extrapyramidal side-effects. The compounds offormula (II) are useful as synthetic intermediate for the compounds offormula (I).

When the compounds of formula (I) of the present invention are used aspharmaceuticals, a therapeutically effective amount of the compounds andadequate pharmacologically acceptable additives such as excipient,carrier, diluent and so on are mixed to be formulated into a form suchas tablets, capsules, granules, syrups, injectable solutions,suppositories, dispersible powders or the like and are administered inthe form mentioned above. The dosage may generally range about 5 toabout 500 mg per day for an adult in a single dose or divided doses inthe case of oral administration.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention will be explained in more detail by the followingexamples, but these examples are not to be construed as limiting thepresent invention. The following compounds obtained can be identified bythe various analysis such as NMR, IR, elemental analysis, massspectrometry and so on.

Reference Example 1

To a solution of 171 g of 2-methylthiophene in 1500 ml of methylenechloride were added dropwise 500 g of tin(IV) chloride and 300 g ofethyl succinyl chloride under ice-cooling and the mixture was stirredfor 1.5 hours. The mixture was poured into water, extracted withchloroform and the organic layer was washed with water, dried overmagnesium sulfate and distilled away. To the residue was added isopropylether and the precipitated crystals were collected by filtration to give299 g of white crystals. The resulting crystals were dissolved in 1600ml of diethylene glycol and 264 g of 100% hydrazine monohydrate was addthereto and the mixture was stirred at 110° C. for 45 minutes. Aftercooling to 60° C., 445 g of potassium hydroxide was added thereto andthe mixture was stirred at 140° C. for 1.5 hours. The mixture was pouredinto water, acidified with hydrochloric acid and extracted with ethylacetate. The organic layer was dried over magnesium sulfate and thesolvent was distilled away. The residue was dissolved in 500 ml ofacetic anhydride, 5 ml of phosphoric acid was added thereto and themixture was refluxed with stirring for 80 minutes. The mixture waspoured into water, made alkaline with potassium carbonate and extractedwith ethyl acetate. The organic layer was washed with water, dried overmagnesium sulfate and concentrated in vacuo. The mixture of 164 g of theresidue, 103 g of hydroxylamine hydrochloride and 124 g of sodiumhydrogencarbonate in 500 ml of ethanol was refluxed with stirring for1.5 hours. The mixture was concentrated in vacuo, water was added to theresidue and extracted with ethyl acetate. The organic layer was washedwith water, dried and distilled away. The residue was recrystallizedfrom ethanol to give 152 g of white crystals. The resulting crystalswere portionwise added to polyphosphoric acid at 60° C. The mixture waspoured into water and extracted with chloroform. The extract was washedwith water, dried over magnesium sulfate and concentrated in vacuo. Theresidue was chromatographed on a silica gel to give 30 g of2-methyl-4,6,7,8-tetrahydro-5H-thieno 3,2-b!azepin-5-one (m.p. 133°-135°C.) and 93 g of 2-methyl-5,6,7,8-tetrahydro-4H-thieno 3,2-c!azepin-4-one(m.p. 119°-120° C.).

Reference Example 2

To a mixture of 61 g of thiophene in 800 ml of tetrahydrofuran was added500 ml of n-butyllithium dropwise at -25° C. and the mixture was stirredfor an hour. To the mixture was added 24.4 g of sulfur at -25° C., themixture was stirred for 1.5 hours and 111.1 g of 3-bromopropionic acidin 50.1 g of potassium carbonate solution was added dropwise thereto,and then the mixture was stirred at room temperature for 4 hours. Theaqueous layer was collected fractionally, washed with toluene, acidifiedwith hydrochloric acid and extracted with chloroform. The organic layerwas washed with water, dried and concentrated to give 135 g of a paleyellow oil. To a solution of 125 g of the oil in 1200 ml of toluene wasadded 153.6 g of trifluoroacetic anhydride dropwise, the mixture wasstirred at room temperature for an hour and stirred at 40° C. forfurther 2 hours. The mixture was poured into ice-cold water andneutralized with sodium hydroxide solution. The toluene layer was washedwith water, dried and concentrated in vacuo to give 103 g of a brownoil. To a solution of 103 g of the oil in 1000 ml of ethanol were added49.9 g of hydroxylamine hydrochloride and 60.3 g of sodiumhydrogencarbonate and the mixture was refluxed with stirring for 2hours. Inorganic substances were filtered off and the filtrate wasconcentrated. To the residue was added isopropyl ether and the crystalswere collected by filtration to give 77 g of white crystals. Theresulting crystals were added portionwise to 100% polyphosphoric acid at70° C. and the mixture was stirred at 80° C. for an hour. After themixture was poured into water, the precipitated crystals were collectedby filtration and recrystallized from ethanol to give 63 g of2,3-dihydrothieno 3,2-f! 1,4!thiazepin-5(4H)-one as pale brown crystals,m.p. 157°-158° C.

EXAMPLE 1

To a mixture of 13 g of 2,3-dihydrothieno 3,2-f! 1,4!thiazepin-5(4H)-oneand 21.5 g of 4-chlorobutyryl chloride in 200 ml of dichloroethane wasadded 21.5 g of aluminum chloride under cooling and the mixture wasstirred for 3 hours. The mixture was poured into ice-cold water andextracted with chloroform. The organic layer was washed with salinesolution, dried over magnesium sulfate and concentrated. The residue wasrecrystallized from ethanol to give 12 g of7-(4-chlorobutyryl)-2,3-dihydrothieno 3,2-f! 1,4!thiazepin-5(4H)-one aswhite crystals, m.p. 124°-125° C.

EXAMPLE 2

To a mixture of 5 g of 2-methyl-5,6,7,8-tetrahydro-4H-thieno3,2-c!azepin-4-one and 5 g of 4-chlorobutyryl chloride in 50 ml ofdichloroethane was added 8.6 g of aluminum chloride under ice-coolingand the mixture was stirred for 3 hours. The mixture was poured intoice-cold water and extracted with chloroform. The organic layer waswashed with saline solution, dried over magnesium sulfate andconcentrated. The residue was recrystallized from ethanol to give 1.2 gof 3-(4-chlorobutyryl)-2-methyl-5,6,7,8-tetrahydro-4H-thieno3,2-c!azepin-4-one as white crystals, m.p. 113°-115° C.

EXAMPLE 3

To a mixture of 5 g of 2-methyl-5,6,7,8-tetrahydro-4H-thieno3,2-b!azepin-5-one and 4.5 g of 3-chloropropionyl chloride in 50 ml ofdichloroethane was added 9.2 g of aluminum chloride and the mixture wasstirred for 3 hours. The mixture was poured into ice-cold water andextracted with chloroform. The organic layer was washed with salinesolution, dried over magnesium sulfate and concentrated. The residue wasrecrystallized from ethanol to give 5.6 g of3-(3-chloropropionyl)-2-methyl-5,6,7,8-tetrahydro-4H-thieno3,2-b!azepin-5-one as white crystals, m.p. 86°-87° C.

EXAMPLE 4

The mixture of 1.0 g of 4-(1,2-benzisothiazol-3-yl)piperazinehydrochloride, 1.5 g of 7-(4-chlorobutyryl)-2,3-dihydrothieno 3,2-f!1,4!thiazepin-5(4H)-one, 2.5 g of potassium carbonate and 0.8 g ofpotassium iodide in 25 ml of N,N-dimethylformamide and 25 ml of toluenewas stirred at 100° C. for 24 hours. After the mixture was cooled in awater bath, water was added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with saline solution, driedover magnesium sulfate and concentrated. The residue was purified bycolumn chromatography on a silica gel, dissolved in isopropyl alcoholand oxalic acid was added thereto to make oxalate. The resultingcrystals were recrystallized from isopropyl alcohol to give 0.12 g of7-(4-(4-(1,2-benzisothiazol-3-yl)piperazin-1-yl)butyryl)-2,3-dihydrothieno3,2-f! 1,4!thiazepin-5(4H)-one oxalate 1/2 hydrate as white crystals,m.p. 118°-120° C.

EXAMPLE 5

The mixture of 2.0 g of 4-(1,2-benzisothiazol-3-yl)piperazinehydrochloride, 2.0 g of3-(4-chlorobutyryl)-2-methyl-5,6,7,8-tetrahydro-4H-thieno3,2-c!azepin-4-one, 2.1 g of potassium carbonate and 1.2 g of potassiumiodide in 15 ml of N,N-dimethylformamide and 15 ml of toluene wasstirred at 60° C. for 3 hours. After the mixture was cooled in a waterbath, water was added thereto and the mixture was extracted with ethylacetate. The organic layer was washed with saline solution, dried overmagnesium sulfate and concentrated. The residue was purified by columnchromatography on a silica gel, dissolved in isopropyl alcohol andethanol-maleic acid was added thereto to make meleate. The resultingcrystals were recrystallized from ethanol to give 0.90 g of3-(4-(4-(1,2-benzisothiazol-3-yl)piperazin-1-yl)butyryl)-2-methyl-5,6,7,8-tetrahydro-4H-thieno3,2-c!azepin-4-one maleate as white crystals, m.p. 150°-152° C.

EXAMPLE 6

The mixture of 2.1 g of 4-(1,2-benzisothiazol-3-yl)piperazinehydrochloride, 2.0 g of3-(3-chloropropionyl)-2-methyl-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one, 2,2 g of potassium carbonate and 1.2 g of potassiumiodide in 15 ml of N,N-dimethylformamide and 15 ml of toluene wasstirred at 60° C. for 5 hours. After the mixture was cooled in a waterbath, water was added thereto and the mixture was extracted with ethylacetate. The organic layer was washed with saline solution, dried overmagnesium sulfate and concentrated. The residue was purified by columnchromatography on a silica gel, dissolved in isopropyl alcohol andcrystallized from isopropyl alcohol-isopropyl ether. The resultingcrystals were recrystallized from ethanol to give 1.30 g of3-(3-(4-(1,2-benzisothiazol-3-yl)piperazin-1-yl)propionyl)-2-methyl-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one as white crystals, m.p. 146°-147° C.

EXAMPLE 7

The mixture of 2.4 g of 4-(bis(4-chlorophenyl)methyl)piperazine, 2.0 gof 7-(4-chlorobutyryl)-2,3-dihydrothieno 3,2-f! 1,4!thiazepin-5(4H)-one,1.9 g of potassium carbonate and 1.2g of potassium iodide in 15 ml ofN,N-dimethylformamide and 15 ml of toluene was stirred at 60° C. for 5hours. After the mixture was cooled in a water bath, water was addedthereto. The precipitated crystals were filtered off and the filtratewas extracted with toluene. The organic layer was washed with salinesolution, dried over magnesium sulfate and concentrated. The residue waspurified by column chromatography on a silica gel and the resultingcrystals were recrystallized from isopropyl alcohol-isopropyl ether togive 0.18 g of7-(4-(4-(bis(4-chlorophenyl)-methyl)piperazin-1-yl)butyryl)-2,3-dihydrothieno3,2-f! 1,4!thiazepin-5(4H)-one as white crystals, m.p. 185°-187° C.(decomposition).

The following compounds can be prepared in a similar manner as theabove.

EXAMPLE 8

2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyryl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one, m.p. 161+-162° C.

EXAMPLE 9

2-(4-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)butyryl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one, m.p. 192°-194° C.

EXAMPLE 10

2-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propionyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one, m.p. 161°-162° C.

EXAMPLE 11

2-(3-(4-(3-trifluoromethylphenyl)piperazin-1-yl)propionyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one, m.p. 137°-138° C.

EXAMPLE 12

7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyryl)-2,3-dihydrothieno3,2-f! 1,4!thiazepin-5(4H)-one, m.p. 197°-198° C.

EXAMPLE 13

2-methyl-3-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyryl)-5,6,7,8-tetrahydro-4H-thieno3,2-c!azepin-4-one hydrochloride, m.p. 220°-222° C.

EXAMPLE 14

7-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-2,3-dihydrothieno3,2-f! 1,4!thiazepin-5(4H)-one, m.p. 186°-187° C.

EXAMPLE 15

2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one, m.p. 210°-212° C. (decomposition).

EXAMPLE 16

2,4-dimethyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one hydrochloride, m.p. 250° C. (decomposition).

EXAMPLE 17

3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-2-methyl-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one oxalate 3/2hydrate, m.p. 115°-118° C.

EXAMPLE 18

2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-3-methyl-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one, m.p. 172°-175° C.

EXAMPLE 19

3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one hydrochloride, m.p. 184°-186° C. (decomposition).

EXAMPLE 20

3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-2-methyl-5,6,7,8-tetrahydro-4H-thieno3,2-c!azepin-4-one oxalate, m.p. 114°-117° C.

EXAMPLE 21

3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)acetyl)-2-methyl-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one hydrochloride 1/2hydrate, m.p. 208°-210° C.(decomposition).

EXAMPLE 22

3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one, m.p. 165°-167° C.

EXAMPLE 23

2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-5,6,7,8-tetrahydro-4H-thieno3,2-c!azepin-4-one, m.p. 182°-184° C.

⊚2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,6,7,8-tetrahydro-5H-thieno3,2-c!azepin-4-one

⊚2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,6,7,8,-tetrahydro-5H-thieno3,2-b!azepin-5-one

⊚7-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-2,3-dihydrothieno3,2-f! 1,4!thiazepin-5(4H)-one

⊚7-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-3,4-dihydrothieno2,3-b! 1,4!thiazepin-2(1H)-one

⊚2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)-1-hydroxybutyl)-5,6,7,8-tetrahydro-4H-thieno3,2-c!azepin-4-one

⊚2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyl)-5,6,7,8-tetrahydro-4H-thieno3,2-c!azepin-4-one

⊚2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)acetyl)-5,6,7,8-tetrahydro-4H-thieno3,2-c!azepin-4-one

⊚2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)acetyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one

⊚2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-5,6,7,8-tetrahydro-4H-thieno3,2-c!azepin-4-one

⊚2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one

⊚ 2-(4-(N,N-dimethylamino)butyryl)-5,6,7,8-tetrahydro-4H-thieno3,2-c!azepin-4-one

⊚ 2-(4-(N,N-dimethylamino)butyryl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one

⊚ 2-(2-(N,N-dimethylamino)acetyl)-5,6,7,8-tetrahydro-4H-thieno3,2-c!azepin-4-one

⊚ 2-(2-(N,N-dimethylamino)acetyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one

⊚2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylthio)-5,6,7,8-tetrahydro-4H-thieno3,2-c!azepin-4-one

⊚2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylsulfinyl)-5,6,7,8-tetrahydro-4H-thieno3,2-c!azepin-4-one

⊚2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylsulfonyl)-5,6,7,8-tetrahydro-4H-thieno3,2-c!azepin-4-one

⊚2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylthio)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one

⊚2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylsulfinyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one

⊚2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylsulfonyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one

⊚2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5-dihydrothieno2,3-b!pyridin-6(7H)-one

⊚2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5-dihydrothieno2,3-c!pyridin-7(6H)-one

⊚2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5-dihydro-7H-thieno3,2-c!pyridin-6-one

⊚2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-6,7-dihydro-4H-thieno2,3-c!pyridin-5-one

⊚2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)acetyl)-4,5-dihydro-7H-thieno3,2-c!pyridin-6-one

⊚2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)acetyl)-6,7-dihydro-4H-thieno2,3-c!pyridin-5-one

⊚2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylthio)-6,7-dihydro-4H-thieno2,3-c!pyridin-5-one

⊚2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylsulfinyl)-6,7-dihydro-4H-thieno2,3-c!pyridin-5-one

⊚2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylsulfonyl)-6,7-dihydro-4H-thieno2,3-c!pyridin-5-one.

Reference Example 3

A mixture of 50 g of 5-methyl-2-thiophenealdehyde and 42 g ofaminoacetoaldehyde dimethyl acetal was stirred at 60°-70° C. for an hourand concentrated to give 71 g of oil. The resulting oil was dissolved in450 ml of methanol, 25 g of sodium borohydride was added thereto undercooling and the mixture was stirred for 10-20 minutes, and thenconcentrated. To the residue was added water and extracted withchloroform. The extract was washed with water, dried over magnesiumsulfate and concentrated. To the residue were added 264 ml of water and132 ml of conc. hydrochloric acid and the mixture was stirred at 50° C.for 2 hours. After cooling, 50 ml of conc. hydrochloric acid and 265 gof tin(II) chloride dihydrate were added thereto and the mixture wasstirred at 60° C. for 2 hours. The mixture was poured into water, madealkaline with 40% sodium hydroxide solution and extracted withchloroform. The organic layer was washed with water, dried overmagnesium sulfate and concentrated. The residue was dissolved in 200 mlof tetrahydrofuran, and 80 ml of triethylamine and 40 ml of aceticanhydride were added thereto under cooling, and then the mixture wasstirred for an hour. The mixture was poured into water, extracted withethyl acetate and the extract was washed with water, dried andconcentrated. The residue was subjected to column chromatography to give27 g of 6-acetyl-4,5,6,7-tetrahydro-2-methylthieno 2,3-c!pyridine.

Reference Example 4

To a solution of 20 g of 4,5,6,7-tetrahydrothieno 3,2-c!pyridine as anoil obtained by a known method in 100 ml of tetrahydrofuran were added30 ml of triethylamine and 15 ml of acetic anhydride under cooling. Themixutre was stirred for an hour, poured into water and extracted withethyl acetate. The extract was washed with water, dried and concentratedto give 10 g of 5-acetyl-4,5,6,7-tetrahydrothieno 3,2-c!pyridine.

Preparative Example 1

To a mixture of 27 g of 6-acetyl-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine and 16 g of acetyl chloride in 250 ml of dichloroethanewas added 42 g of aluminum chloride under cooling and the mixture wasstirred for 30 minutes. The mixture was poured into water and extractedwith chloroform. The organic layer was washed with water, dried overmagnesium sulfate and concentrated. The residue was dissolved in 300 mlof methanol, 20 g of bromine was added thereto at 30° C. and the mixturewas stirred for 2 hours. The mixture was poured into water and extractedwith ethyl acetate. The organic layer was washed with water, dried andconcentrated to give 28 g of6-acetyl-3-bromoacetyl-4,5,6,7-tetrahydro-2-methylthieno 2,3-c!pyridine.

Preparative Example 2

A mixture of 28 g of6-acetyl-3-bromoacetyl-4,5,6,7-tetrahydro-2-methylthieno 2,3-c!pyridinein 42 ml of triethylsilane and 140 ml of trifluoroacetic acid wasstirred at room temperature for 5 hours. The mixture was poured intowater, made alkaline and extracted with ethyl acetate. The organic layerwas washed with water, dried and concentrated. To the residue was addedisopropyl ether and the precipitated crystals were collected byfiltration to give 14 g of6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine as white crystals, m.p. 93°-95° C.

The following compounds were prepared in a similar manner as the above.Figures mean δ value of ¹ H-NMR (CDCl₃).

⊚ 5-acetyl-2-(2-bromoethyl)-4,5,6,7-tetrahydrothieno 3,2-c!pyridine

6.66(s, 1H), 4.60(d,2H), 4.00-3.00(m,6H), 2.80(b,2H), 2.15(s,3H)

⊚ 6-acetyl-3-(3-chloropropyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine

4.66(d,2H), 4.00-3.30(m,4H), 2.50(b,4H), 2.33(s,3H), 2.15(s,3H),1.50(m,2H)

⊚ 6-acetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydro-3-methylthieno2,3-c!pyridin

4.60(d,2H), 4.00-3.40(m,4H), 3.15(t,2H), 2.50(b,4H), 2.15(s,3H),2.05(s,3H)

⊚ 6-acetyl-3-(4-chlorobutyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine

4.66(d,2H), 4.00-3.40(m,4H), 2.70-2.30(b,4H), 2.33(s,3H), 2.15(s,3H),2.00-1.30(m,4H),

⊚ 6-acetyl-2-(2-bromoethyl)-4,5,6,7-tetrahydrothieno 2,3-c!pyridine

6.70(s,1H), 4.60(d,2H), 4.00-3.00(m,6H), 2.66(b,2H), 2.10(s,3H)

⊚ 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine

4.65(d,2H), 4.05-3.40(m+t,4H), 2.95(t,2H), 2.65(b,2H), 2.40(s,3H),2.20(s,3H)

⊚ 3,6-bisacetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydro 2,3-c!pyridine

4.66(d,2H), 4.00-3.50(m+t,4H), 3.40(t,2H), 2,85(b,2H), 2.50(s,3H),2.15(s,3H)

⊚ 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-propylthieno2,3-c!pyridine

4.66(d,2H), 4.00-3.33(m+t,4H), 3.00-2.33(m,6H), 2.15(s,3H), 1.65(m,2H),1.00(t,3H)

⊚ 6-acetyl-3-chloroacetyl-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine

4.75(d,2H), 4.50(s,2H), 3.75(t,2H), 2.65(t,2H), 2.50(s,3H),2.20(s,3H).

EXAMPLE 24

A mixture of 5.9 g of6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine, 5 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinehydrochloride, 6.7 g of potassium carbonate and 3.2 g of potassiumiodide in 50 ml of dimethylformamide and 50 ml of toluene was stirred at50° C. for 7 hours and poured into water. The toluene layer was washedwith water, dried over magnesium sulfate and concentrated. The residuewas purified by column chromatography on a silica gel and crystallizedfrom isopropyl ether. The resulting crystals were recrystallized fromacetonitrile to give6-acetyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine, m.p. 70°-75° C.

EXAMPLE 25

A mixture of 4 g of6-acetyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine in 4ml of conc. sulfuric acid and 80 ml of water wasrefluxed under heating for 3 hours. The mixture was poured into water,made alkaline and extracted with chloroform. The organic layer waswashed with water, dried over magnesium sulfate and concentrated. To theresidue was added isopropyl ether and the crystals were collected byfiltration to give3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine, m.p. 88°-90° C.

EXAMPLE 26

To a mixture of 0.5 g of3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine in 0.5 ml of triethylamine and 10 ml of chloroform wasadded 0.18 g of benzoyl chloride under cooling and the mixture wasstirred for an hour, and then poured into water. The organic layer waswashed with water, dried and concentrated. The residue was purified bycolumn chlomatogaphy to give 0.4 g of6-benzoyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine as an oil, m.p. 192°-195° C. as oxalate 1/4hydratethereof.

EXAMPLE 27

The reaction and procedure were conducted in a similar manner as inExample 24 using 0.48 g of6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylothieno2,3-c!pyridine and 0.5 g of4-((6,7-dimethoxy-1,2-benzisoxazol-3-yl)methyl)piperidine hydrochlorideto give 0.4 g of6-acetyl-3-(2-(4-((6,7-dimethoxy-1,2-benzisoxazol-3-yl)methyl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine as an oil, m.p. 197°-200° C. as oxalate thereof.

EXAMPLE 28

The reaction and procedure were conducted in a similar manner as inExample 26 using 0.19 g of cyclohexanecarbonyl chloride in stead ofbenzoyl chloride to give 0.06 g of6-cyclohexylcarbonyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine as an oil, m.p. 205°-208° C. as oxalate 1/2hydratethereof.

EXAMPLE 29

The reaction and procedure were conducted in a similar manner as inExample 24 using 1.4 g of6-acetyl-3-(4-chlorobutyryl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine and 1.3 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinehydrochloride to give 1.4 g of6-acetyl-3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine as an oil.

¹ H-NMR(CDCl₃) δ:1.85-2.30(m,8H), 2.15(s,3H), 2.30-2.70(m,2H),2.60(s,3H) 2.70-3.30(m,5H), 3.65(m,4H), 4.60(d,2H), 7.05(dt,1H),7.25(dd,1H), 7.70(dd,1H).

EXAMPLE 30

The reaction and procedure were conducted in a similar manner as inExample 24 using 1.5 g of6-acetyl-3-(4-chlorobutyryl-4,5,6,7-tetrahydro-2-ethylthieno2,3-c!pyridine and 1.2 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinehydrochloride to give 0.7 g of6-acetyl-3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydro-2-ethylthieno2,3-c!pyridine as an oil, m.p. 93°-95° C. as oxalate 1/4hydrate thereof.

EXAMPLE 31

The reaction and procedure were conducted in a similar manner as inExample 24 using 4.0 g of6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydrothieno 2,3-c!pyridine and3.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride togive 3.3 g of6-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine as white crystals, m.p. 130°-132° C.

EXAMPLE 32

The reaction and procedure were conducted in a similar manner as inExample 24 using 2.5 g of6-acetyl-3-(2-bromoethyl)-2-ethyl-4,5,6,7-tetrahydrothieno2,3-c!pyridine and 2.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinehydrochloride to give 2.2 g of6-acetyl-2-ethyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine as an oil, m.p. 191°-201° C. as oxalate 1/2hydratethereof.

EXAMPLE 33

The reaction and procedure were conducted in a similar manner as inExample 24 using 0.7 g of5-acetyl-2-(2-bromoethyl)-4,5,6,7-tetrahydrothieno 2,3-c!pyridine and0.61 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride togive 0.7 g of5-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine as an oil, m.p. 170°-172° C. as oxalate thereof.

EXAMPLE 34

The reaction and procedure were conducted in a similar manner as inExample 24 using 0.7 g of6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine and 0.6 g of 4-(bis(4-fluorophenyl)-methylene)piperidineto give 0.5 g of6-acetyl-3-(2-(4-(bis(4-fluorophenyl)methylene)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine as an oil, m.p. 209°-211° C. as axalate thereof.

EXAMPLE 35

The reaction and procedure were conducted in a similar manner as inExample 24 using 1.0 g of6-acetyl-3-chloroacetyl-4,5,6,7-tetrahydro-2-methylthieno 2,3-c!pyridineand 0.95 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochlorideto give 0.9 g of6-acetyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)-1-oxoethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine as an oil, m.p. 92°-94° C. as 3/2oxalate 1/2hydratethereof.

EXAMPLE 36

The reaction and procedure were conducted in a similar manner as inExample 24 using 1.7 g of6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-propylthieno2,3-c!pyridine and 1.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinehydrochloride to give 0.7 g of6-acetyl-2-propyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine as an oil, m.p. 178°-180° C. (decomposition) as oxalate1/2hydrate thereof.

EXAMPLE 37

The reaction and procedure were conducted in a similar manner as inExample 24 using 1.0 g of6-acetyl-3-(4-chlorobutyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine and 0.9 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinehydrochloride to give 0.5 g of6-acetyl-3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine as an oil, m.p. 158°-160° C. as 3/2oxalate thereof.

EXAMPLE 38

The reaction and procedure were conducted in a similar manner as inExample 24 using 2.0 g of6-acetyl-(3-chloropropyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine and 2.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinehydrochloride to give 0.5 g of 6-acetyl-3-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propionyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine as an oil, m.p. 180°-182° C. as oxalate thereof.

EXAMPLE 39

To a solution of 0.5 g of3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine hydrochloride in ethanol was added 0.3 ml of 37%formaldehyde solution and the mixture was stirred at room temperaturefor an hour. To the mixture was added 0.2 g of sodium cyanoborohydride,the mixture was stirred for an hour, and then concentrated. To theresidue was added water and extracted with chloroform. The extract waswashed with water, dried and concentrated in vacuo. The residue waspurified by column chromatography and recrystallized from isopropylether to give2,6-dimethyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine 1/2hydrate as white crystals, m.p. 100°-103° C.

EXAMPLE 40

A mixture of 0.8 g of6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine and 20 ml of 16.8% dimethylamine-ethanol solution in apressure bottle was stirred at 80° C. for 5 hours and then the solventwas distilled away. To the residue was added water and extracted withethyl acetate. The extract was washed with water, dried and concentratedin vacuo to give 0.4 g of6-acetyl-3-(2-dimethylaminoethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine as an oil.

¹ H-NMR(CDCl₃) δ:2.17(s,3H), 2.30(s,6H), 2.40(s,3H), 2.50-2.80 (m,6H),3.80(m,2H), 4.66(d,2H).

EXAMPLE 41

The reaction and procedure were conducted in a similar manner as inExample 40 using 2.3 g of5-acetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydrothieno 3,2-c!pyridine togive 5-acetyl-2-(2-dimethylaminoethyl)-4,5,6,7-tetrahydrothieno3,2-c!pyridine hydrochloride 1/4hydrate, m.p. 201°-203° C.(decomposition).

EXAMPLE 42

The reaction and procedure were conducted in a similar manner as inExample 24 using 1.0 g of6-acetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydro-3-methylthieno2,3-c!pyridine and 1.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinehydrochloride to give6-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-3-methylthieno2,3-c!pyridine as an oil.

¹ H-NMR(CDCl₃) δ:1.80-3.50(m,15H), 2.10(s,3H), 2.25(s,3H), 3.80(m,2H),4.70(d,2H), 7.10(dt,1H), 7.30(dd,1H), 7.75(dd,1H).

EXAMPLE 43

The reaction and procedure were conducted in a similar manner as inExample 24 using 2.2 g of6-acetyl-2-(4-chlorobutyryl)-4,5,6,7-tetrahydrothieno 2,3-c!pyridine and2.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride togive 1.3 g of6-acetyl-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine as white crystals, m.p. 145°-147° C.

EXAMPLE 44

The reaction and procedure were conducted in a similar manner as inExample 26 using 0.12 g of propionyl chloride instead of benzoylchloride to give 0.4 g of3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methyl-6-propionylthieno2,3-c!pyridine as an oil, m.p. 192°-195° C. (decomposition) as oxalate1/2 hydrate thereof.

EXAMPLE 45

The reaction and procedure were conducted in a similar manner as inExample 26 using 0.15 g of isobutyryl chloride instead of benzoylchloride to give 0.4 g of3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-6-isobutyryl-2-methylthieno2,3-c!pyridine as an oil, m.p.200° C. (decomposition) as oxalate1/2hydrate thereof.

EXAMPLE 46

The reaction and procedure were conducted in a similar manner as inExample 26 using 0.14 g of cyclopropylcarbonyl chloride instead ofbenzoyl chloride to give 0.4 g of6-cyclopropylcarbonyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine as an oil, m.p. 188°-190° C. (decomposition) as oxalate1/4hydrate thereof.

EXAMPLE 47

The reaction and procedure were conducted in a similar manner as inExample 24 using 1.5 g of3,6-diacetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydrothieno 2,3-c!pyridineand 1.3 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochlorideto give3,6-diacetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl-4,5,6,7-tetrahydrothieno2,3-c!pyridine as an oil.

¹ H-NMR(CDCl₃) δ:1.80-2.60(m,7H), 2.20(s,3H), 2.50(s,3H), 2.60-3.40(m,8H), 3.65(m,2H), 4.60(d,2H), 7.05(dt,1H), 7.25(dd,1H), 7.70(dd,1H).

EXAMPLE 48

The reaction and procedure were conducted in a similar manner as inExample 24 using 2.0 g of5-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno3,2-c!pyridine and 1.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinehydrochloride to give 0.25 g of 5-acetyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno3,2-c!pyridine as an oil.

¹ H-NMR(CDCl₃) δ:1.60-2.50(m,8H), 2.20(s,3H), 2.40(s,3H), 2.50-2.90(m,4H), 3.16(m,3H), 3.80(m,2H), 4.50(d,2H), 7.05(dt,1H), 7.25(dd,1H),7.70(dd,1H).

EXAMPLE 49

The reaction and procedure were conducted in a similar manner as inExample 24 using 1.4 g of6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine and 0.9 g of 4-(1,2-benzisothiazol-3-yl)piperazine togive 1.0 g of6-acetyl-3-(2-(4-(1,2-benzisothiazol-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine as an oil, m.p. 190°-192° C. (decomposition) as oxalatethereof.

EXAMPLE 50

The reaction and procedure were conducted in a similar manner as inExample 24 using 1.6 g of5-acetyl-3-(4-chlorobutyryl)-4,5,6,7-tetrahydro-2-methylthieno3,2-c!pyridine and 1.4 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinehydrochloride to give 0.6 g of5-acetyl-3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydro-2-methylthieno3,2-c!pyridine as an oil.

¹ H-NMR(CDCl₃) δ:1.80-3.30(m,16H), 2.02(s,3H), 2.18(s,3H), 3.75(m,3H),4.70(d,2H). 7.04(dd,2H), 7.70(dd,1H).

EXAMPLE 51

A mixture of 334 mg of6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine, 420 mg of4-(6-fluoro-1-(4-fluorophenyl)-1H-indazol-3-yl)piperidine hydrochloride,500 mg of potassium carbonate and 216 mg of potassium iodide in 10 ml ofdimethylformamide and 10 ml of toluene was stirred at 8520 C. for 8hours and concentrated in vacuo. To the residue were added ethyl acetateand water, and separated. The ethyl acetate layer was washed with water,dried over magnesium sulfate and concentrated in vacuo. The residue waspurified by column chromatography on a silica gel to give 360 mg of6-acetyl-3-(2-(4-(6-fluoro-1-(4-fluorophenyl)-1H-indazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine as an oil, m.p. 193°-196° C. as oxalate thereof.

EXAMPLE 52

A mixture of 334 mg of6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine, 308 mg of 4-(5-fluoro-1,2-benzisoxazol-3-yl)piperidinehydrochloride, 500 mg of potassium carbonate and 220 mg of potassiumiodide in 10 ml of dimethylformamide and 10 ml of toluene was stirred at90° C. for 25 hours and concentrated in vacuo. To the residue were addedethyl acetate and water and separated. The ethyl acetate layer waswashed with water, dried over magnesium sulfate and concentrated invacuo. The residue was purified by column chromatography on a silica gelto give 100 mg of6-acetyl-3-(2-(4-(5-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine as an oil, m.p. 167°-172° C. as oxalate thereof.

EXAMPLE 53

A mixture of 210 mg of6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine, 200 mg of 4-(6-fluorobenzo(b)thiophen-3-yl)piperidinehydrochloride, 250 mg of potassium carbonate and 140 mg of potassiumiodide in 5 ml of dimethylformamide and 5 ml of toluene was stirred at90° C. for 22 hours and concentrated in vacuo. To the residue were addedethyl acetate and water, and separated. The ethyl acetate layer waswashed with water, dried over magnesium sulfate and concentrated invacuo. The residue was purified by column chromatography on a silica gelto give 160 mg of6-acetyl-3-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine as an oil.

¹ H-NMR(CDCl₃) δ:2.20(s,3H), 2.40(s,3H), 3.10(m,2H), 1.8-2.8 (m,13H),3.75(m,2H), 4.60(d,2H), 7.02(s,1H), 7.10(dt,1H), 7.50 (dd,1H),7.70(dd,1H) m.p. 223°-225° C. as oxalate thereof.

EXAMPLE 54

A mixture of 514 mg of6-acety-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine, 511 mg of 4-(6-fluoro-1H-indazol-3-yl)piperidinehydrochloride, 690 mg of potassium carbonate and 365 mg of potassiumiodide in 10 ml of dimethylformamide and 10 ml of toluene was stirred at90° C. for 22 hours and concentrated in vacuo. To the residue were addedethyl acetate and water, and separated. The ethyl acetate layer waswashed with water, dried over magnesium sulfate and concentrated invacuo. The residue was purified by column chromatography on a silica geland recrystallized from the mixture of diisopropyl ether and isopropylalcohol to give 170 mg of6-acetyl-3-(2-(4-(6-fluoro-1H-indazol-3-yl)piperidin-1-yl)ethyl-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine monohydrate, m.p. 116°-119° C.

EXAMPLE 55

A mixture of 590 mg of6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine, 580 mg of 4-(6-fluoro-1-methyl-1H-indazol-3-yl)piperidine, 780 mg of potassium carbonate and 415 mg of Potassium iodidein 10 ml of dimethylformamide and 10 ml of toluene was stirred at 90° C.for 22 hours and concentrated in vacuo. To the residue were added ethylacetate and water, and separated. The ethyl acetate layer was washedwith water, dried over magnesium sulfate and concentrated in vacuo. Theresidue was purified by column chromatography on a silica gel to give540 mg of6-acetyl-3-(2-(4-(6-fluoro-1-methyl-1H-indazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno 2,3-c!pyridine as an oil, m.p.213°-216° C. as oxalate thereof.

EXAMPLE 56

To a solution of 2 g of 4,5,6,7-tetrahydro-5H-thieno 2,3-c!azepin-8-oneand 2 g of chloroacetyl chloride in 25 ml of dichloromethane was added4.8 g of aluminum chloride. The mixture was stirred for 30 minutes,refluxed under heating for an hour and then poured into water. Theprecipitated crystals were collected by filtration and washed withisopropyl alcohol to give 2 g of2-chloroacetyl-4,5,6,7-tetrahydro-8H-thieno 2,3-c!azepin-8-one, m.p.221°-223° C. (decomposition).

EXAMPLE 57

A mixture of 1.9 g of 2-chloroacetyl-4,5,6,7-tetrahydro-8H-thieno2,3-c!azepin-8-one in 5.4 ml of triethylsilane and 15 ml oftrifluoroacetic acid was stirred at 50° C. for 12 hours. The mixture waspoured into water, alkali fled and extracted with ethyl acetate. Theexract was washed with water, dried and concentrated. The residue waspurified by column chromatography on a silica gel to give 0.85 g of2-chloroethyl-4,5,6,7-tetrahydro-8H-thieno 2,3-c!azepin-8-one as whitecrystals, m.p. 156°-158° C.

EXAMPLE 58

A mixture of 800 mg of 2-chloroethyl-4,5,6,7-tetrahydro-8H-thieno2,3-c!azepin-8-one, 920 mg of4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride, 1.45 g ofpotassium carbonate and 580 mg of potassium iodide in 10 ml ofdimethylformamide and 10 ml of toluene was stirred at 90° C. for 22hours and concentrated in vacuo. To the residue were added ethyl acetateand water, and separated. The ethyl acetate layer was washed with water,dried over magnesium sulfate and concentrated in vacuo. The residue waspurified by column chromatography on a silica gel and recrystallizedfrom ethyl acetate to give 0.65 g of2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-8H-thieno2,3-c!azepin-8-one, m.p. 192°-194° C.

EXAMPLE 59

To a solution of 2 g of 4,5,6,7-tetrahydro-8H-thieno 2,3-c!azepin-8-oneand 2.5 g of 4-chlorobutyryl chloride in 25 ml of dichloromethane wasadded 4.8 g of aluminum chloride under cooling. The mixture was stirredfor 80 minutes, refluxed under heating and poured into water, and thenextracted with chloroform. The extract was washed with water, dried overmagnesium sulfate and concentrated. The residue was crystallized fromethyl acetate-isopropyl ether to give 1.2 g of2-(4-chlorobutyryl)-4,5,6,7-tetrahydro-8H-thieno 2,3-c!azepin-8-one aswhite crystals, m.p. 163°14 165° C.

EXAMPLE 60

A mixture of 1.1 g of 2-(4-chlorobutyryl)-4,5,6,7-tetrahydro-8H-thieno2,3-c!azepin-8-one, 1.1 g of4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride, 1.68 g ofpotassium carbonate and 670 mg of potassium iodide in 10 ml ofdimethylformamide and 10 ml of toluene was stirred at 90° C. for 22hours and concentrated in vacuo. To the residue were added ethyl acetateand water, and separated. The ethyl acetate layer was washed with water,dried over magnesium sulfate and concentrated in vacuo. The residue waspurified by column chromatography on a silica gel and recrystallizedfrom ethyl acetate-isopropyl ether to give 0.55 g of2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydro-8H-thieno2,3-c!azepin-8-one 1/2hydrate, m.p. 186°-187° C.

EXAMPLE 61

To a mixture of 6.7 g of 4,5,6,7-tetrahydro-8H-thieno 2,3-c!azepin-8-oneand 4.5 g of sodium borohydride in 70 ml of tetrahydrofuran was addedboron trifluoride-ether complex dropwise under ice-cooling and themixture was refluxed under heating for an hour. The mixture was pouredinto water, washed with chloroform, made alkaline with 10% potassiumhydroxide solution and extracted with chloroform. The extract was washedwith water, dried and concentrated to give 4.1 g of5,6,7,8-tetrahydro-4H-thieno 2,3-c!azepine as an oil.

EXAMPLE 62

To a mixture of 4 g of 5,6,7,8-tetrahydro-4H-thieno 2,3-c!azepine and 4g of pyridine in 20 ml of chloroform was added 4.1 g of acetic anhydrideunder ice-cooling and the mixture was stirred at room temperature for anhour. The mixture was poured into water and extracted with chloroform.The extract was washed with water, dried and concentrated to give 4 g of7-acetyl-5,6,7,8-tetrahydro-4H-theino 2,3-c!azepine as an oil.

EXAMPLE 63

To a solution of 2 g of 7-acetyl-5,6,7,8-tetrahydro-4H-thieno2,3-c!azepine and 1.7 g of chloroacetyl chloride in 25 ml ofdichloromethane was added 4.8 g of aluminum chloride under ice-cooling.The mixture was stirred for 30 minutes and refluxed under heating for anhour. The mixture was poured into water and extracted with chloroform.The extract was washed with water, dried over magnesium sulfate andconcentrated to give 2.2 g of7-acetyl-2-chloroacetyl-5,6,7,8-tetrahydro-4H-thieno 2,3-c!azepine as anoil.

EXAMPLE 64

A mixture of 2.1 g of7-acetyl-2-chloroacetyl-5,6,7,8-tetrahydro-4H-thieno 2,3-c!azepine in5.4 ml of triethylsilane and 15 ml of trifluoroacetic acid was stirredat room temperature for 12 hours. The mixture was poured into water,made alkaline and extracted with ethyl acetate. The exract was washedwith water, dried and concentrated. The residue was purified by columnchromatography on a silica gel to give 1.8 g of7-acetyl-2-chloroethyl-5,6,7,8-tetrahydro-4H-thieno 2,3-c!azepine as anoil.

EXAMPLE 65

A mixture of 1.6 g of7-acetyl-2-chloroethyl-5,6,7,8-tetrahydro-4H-thieno 2,3-c!azepine, 1.8 gof 4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidine hydrochloride, 2.6 g ofpotassium carbonate and 1 g of potassium iodide in 15 ml ofdimethylformamide and 15 ml of toluene was stirred at 90° C. for 5 hoursand concentrated in vacuo. To the residue were added ethyl acetate andwater, and separated. The ethyl acetate layer was washed with water,dried over magnesium sulfate and concentrated in vacuo. The residue waspurified by column chromatograhy on a silica gel to give 1.5 g of7-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-5,6,7,8-tetrahydro-4H-thieno2,3-c!azepine as an oil. The oil was treated with hydrochloric acid inisopropyl alcohol and recrystallized from ethanol-isopropyl ether togive7-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-5,6,7,8-tetrahydro-4H-thieno2,3-c!azepine hydrochloride 3/2hydrate, m.p. 210° C. (decomposition).

EXAMPLE 66

To a solution of 2.5 g of 7-acetyl-5,6,7,8-tetrahydro-4H-thieno-2,3-c!azepine and 2.7 g of 4-chlorobutyryl chloride in 25 ml ofdichloromethane was added 6.0 g of aluminum chloride under ice-cooling.The mixture was stirred for 30 minutes, poured into water and extractedwith chloroform. The extract was washed with water, dried over magnesiumsulfate and concentrated. The residue was purified by columnchromatography on a silica gel to give 2.9 g of7-acetyl-2-(4-chlorobutyryl)-5,6,7,8-tetrahydro-4H-thieno 2,3-c!azepineas an oil.

EXAMPLE 67

A mixture of 2.8 g of7-acetyl-2-(4-chlorobutyryl)-5,6,7,8-tetrahydro-4H-thieno 2,3-c!azepine,2.6 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride, 3.9g of potassium carbonate and 1.55 g of potassium iodide in 30 ml ofdimethylformamide and 30 ml of toluene was stirred at 70° C. for 20hours and concentrated in vacuo. To the residue were added ethyl acetateand water, and separated. The ethyl acetate layer was washed with water,dried over magnesium sulfate and concentrated in vacuo. The residue waspurified by column chromatography on a silica gel to give 3.0 g of7-(acetyl-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-5,6,7,8-tetrahydro-4H-thieno2,3-c!azepine as an oil. The oil was treated with hydrochloric acid inisopropyl alcohol and recrystallized from ethanol-ethyl acetate to give7-acetyl-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-5,6,7,8-tetrahydro-4H-thieno2,3-c!azepin hydrochloride, m.p. 230° C. (decomposition).

EXAMPLE 68

The reaction and procedure were conducted in a similar manner as inExample 24 using 1.6 g of5-acetyl-3-(4-chlorobutyryl)-4,5,6,7-tetrahydro-2-methylthieno3,2-c!pyridine and 1.4 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinehydrochloride to give 0.6 g of5-acetyl-3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydro-2-methylthieno3,2-c!pyridine as an oil, m.p. 116°-118° C. as an oxalate monohydratethereof.

EXAMPLE 69

The reaction and procedure were conducted in a similar manner as inExample 14 using 1.0 g of6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine and 0.88 g of 1-(1,2-benzoisothiazol-3-yl)piperazine togive 1.0 g of6-acetyl-3-(2-(4-(1,2-benzisothiazol-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine as an oil, m.p. 190°-192° C. (decomposition) as anoxalate 1/2hydrate thereof.

EXAMPLE 70

The reaction and procedure were conducted in a similar manner as inExample 24 using 0.9 g of6-acetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydrothieno 2,3-c!pyridine and1.0 g of 4-(5-chloro-1,2-benzisoxazol-3-yl)piperidine hydrochloride togive 0.7 g of6-acetyl-2-(2-(4-(5-chloro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine as an oil, m.p. 122°-124° C. (decomposition) as ahydrochloride thereof.

EXAMPLE 71

The reaction and procedure were conducted in a similar manner as inExample 24 using 0.2 g of6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine and 0.2 g of 1-(6-chlorobenzothiazol-2-yl)piperazine togive 0.04 g of6-acetyl-3-(2-(4-(6-chlorobenzothiazol-2-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine as an oil, m.p. 180° C. (decomposition) as an oxalatethereof.

EXAMPLE 72

The reaction and procedure were conducted in a similar manner as inExample 24 using 2.0 g of5-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno3,2-c!pyridine and 1.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinehydrochloride to give 0.25 g of5-acetyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno3,2-c!pyridine as an oil, m.p. 198°-200° C. (decomposition) as anoxalate thereof.

EXAMPLE 73

The reaction and procedure were conducted in a similar manner as inExample 24 using 0.7 g of6-acetyl-2-(2-chloroethyl)-3-ethyl-4,5,6,7-tetrahydrothieno2,3-c!pyridine and 0.67 g of4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.5 gof6-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-3-ethyl-4,5,6,7-tetrahydrothieno2,3-c!pyridine as an oil, m.p. 165°-167° C. (decomposition) ashydrochloride dihydrate thereof.

EXAMPLE 74

The reaction and procedure were conducted in a similar manner as inExample 24 using 1.8 g of5-acetyl-2-(4-chlorobutyryl)-4,5,6,7-tetrahydrothieno 3,2-c!pyridine and1.6 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride togive 1.0 g of5-acetyl-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydro-thieno3,2-c!pyridine as an oil, m.p. 235° C. as hydrochloride 1/2hydratethereof.

EXAMPLE 75

The reaction and procedure were conducted in a similar manner as inExample 24 using 1.1 g of2-(4-chlorobutyryl)-5,6,7,8-tetrahydro-4H-thieno 3,2-c!azepin-4-one and1.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride togive 0.21 g of2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-5,6,7,8-tetrahydro-4H-thieno3,2-c!azepin-4-one, m.p. 142°-143° C.

EXAMPLE 76

To a solution of 0.4 g of3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)acetyl)-2-methyl-5,6,7,8-tetrahydro-4H-thieno3,2-c!azepin-4-one (m.p. 175°-176° C. as oxalate thereof) in 20 ml ofmethanol was added 0.5 g of sodium borohydride under cooling. Themixture was stirred for 10 minutes and concentrated. Water was addedthereto and the solution was extracted with ethyl acetate. The extractwas washed with water, dried and the solvent was distilled away. Theresidue was treated with fumaric acid in ethanol and recrystallized fromethanol to give 0.22 g of3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)-1-hydroxyethyl)-2-methyl-5,6,7,8-tetrahydro-4H-thieno3,2-c!azepin-4-one difumarate monohydrate, m.p. 116°-118° C.

EXAMPLE 77

The reaction and procedure were conducted in a similar manner as inExample 24 using 0.5 g of6-acetyl-3-bromo-2-(2-chloroethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine and 0.4 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinehydrochloride to give 0.05 g of6-acetyl-3-bromo-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine as an oil, m.p. 114°-117° C. as an oxalate thereof.

EXAMPLE 78

The reaction and procedure were conducted in a similar manner as inExample 24 using 0.5 g of 2-(2-chloroethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one and 0.5 g of4-(6-fluorobenzo(b)thiophen-3-yl)piperidine hydrochloride to give 0.2 gof2-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one, m.p. 191°-193° C.

EXAMPLE 79

The reaction and procedure are conducted in a similar manner as inExample 24 using6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-ethylthieno2,3-c!pyridine and 4-(6-fluorobenzo(b)thiophen-3-yl)piperidinehydrochloride to give6-acetyl-3-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-ethylthieno2,3-c!pyridine.

EXAMPLE 80

The reaction and procedure are conducted in a similar manner as inExample 24 using 6-acetyl-2-(4-chlorobutyryl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine and 4-(6-fluorobenzo(b)thiophen-3-yl)piperidinehydrochloride to give6-acetyl-2-(4-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 81

The reaction and procedure are conducted in a similar manner as inExample 24 using6-acetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydro-3-methylthieno2,3-c!pyridine and 4-(6-fluorobenzo(b)thiophen-3-yl)piperidinehydrochloride to give6-acetyl-2-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-3-methylthieno2,3-c!pyridine.

EXAMPLE 82

A mixture of 0.5 g of2-((3-chloropropyl)thio)-4-oxo-4,5,6,7-tetrahydrobenzo(b)thiophene, 0.5g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride, 0.6 gof potassium carbonate and 0.4 g of potassium iodide in 10 ml ofdimethylformamide and 10 ml of toluene was mixed at 100° C. for 4 hoursand poured into water. The toluene layer was washed with water, driedover magnesium sulfate and concentrated. The residue was purified bycolumn chromatography on a silica gel to give 0.5 g of2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylthio)-4-oxo-4,5,6,7-tetrahydrobenzo(b)-thiophene.The resulting compound was dissolved in 20 ml of ethanol, and 0.1 g ofhydroxylamine hydrochloride and 0.12 g of sodium hydrogencarbonate wereadded thereto. After the mixture was refluxed for 3 hours, the solventwas distilled away in vacuo and water was added to the residue, and thenextracted with ethyl acetate. The extract was washed with water, driedover magnesium sulfate and concentrated. To the residue was addedisopropyl ether to give 0.5 g of an oxime compound as crystals. Amixture of 0.35 g of the oxime compound and 3.5 g of 115% polyphosphoricacid was stirred at 100° C. for 5 hours, poured into water and extractedwith chloroform. The extract was washed with water, dried andconcentrated. The residue was separated and purified by columnchromatography on a silica gel and each of resulting crystals wasrecrystallized from isopropyl ether to give 0.06 g of2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylthio)-5,6,7,8-tetrahydro-4H-thieno3,2-c!azepin-4-one, m.p. 119°-121° C. and 0.019 g of2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylthio)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one, m.p. 125°-127° C.

EXAMPLE 83

A mixture of 1.0 g of2-(2-chloroethyl)-3-ethyl-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one, 1.0 g of4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride, 4.0 g ofpotassium carbonate and 1.5 g of potassium iodide in 25 ml ofdimethylformamide and 25 ml of toluene was stirred at 100° C. for 3hours and poured into water. The toluene layer was washed with water,dried over magnesium sulfate and concentrated. The residue was purifiedby column chromatography on a silica gel and recrystallized fromisopropyl alcohol to give 0.45 g of3-ethyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one 3/4hydrate, m.p. 115°-117° C.

EXAMPLE 84

A mixture of 0.7 g of6-acetyl-2-(2-chloroethyl)-3-ethyl-4,5,6,7-tetrahydrothieno2,3-c!pyridine, 0.7 g of 4-(6-fluorobenzo(b)thiophen-3-yl)piperidinehydrochloride, 1.8 g of potassium carbonate and 0.6 g of potassiumiodide in 25 ml of dimethylformamide and 25 ml of toluene was stirred at70° C. for 7 hours and poured into water. The toluene layer was washedwith water, dried over magnesium and concentrated. The residue waspurified by column chromatography on a silica gel and dissolved inethanol to convert hydrochloride thereof, and then recrystallized frommethanol to give 0.45 g of6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo-(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine hydrochloride, m.p. 240° C. (decomposition).

EXAMPLE 85

A mixture of 1.0 g of6-acetyl-2-(2-chloroethyl)-3-ethyl-4,5,6,7-tetrahydrothieno2,3-c!pyridine, 0.95 g of 4-(6-fluorobenzo(b)furan-3-yl)piperidinehydrochloride, 3.0 g of potassium carbonate and 1.0 g of potassiumiodide in 25 ml of dimethylformamide and 25 ml of toluene was stirred at70° C. for 7 hours and poured into water. The toluene layer was washedwith water, dried over magnesium sulfate and concentrated. The residuewas purified by column chromatography on a silica gel and dissolved inethanol to convert hydrochloride thereof, and then recrystallized fromisopropyl alcohol to give 0.5 g of6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-thieno2,3-c!pyridine hydrochloride, m.p. 205° C. (decomposition).

EXAMPLE 86

A mixture of 0.5 g of6-acetyl-2-(2-chloroethyl)-3-ethyl-4,5,6,7-tetrahydrothieno2,3-c!pyridine, 0.5 g of 4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidinehydrochloride, 1.5 g of potassium carbonate and 0.5 g of potassiumiodide in 25 ml of dimethylformamide and 25 ml of toluene was stirred at70° C. for 7 hours and poured into water. The toluene layer was washedwith water, dried over magnesium sulfate and concentrated. The residuewas purified by column chromatography on a silica gel to give 0.5 g of6-acetyl-3-ethyl-2-(2-(4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine as an oil.

¹ H-NMR (CDCl₃) δ:1.10 (t,3H), 2.00-2.40 (m,4H), 2.20 (d,3H), 2.50(q,2H), 2.60-2.70 (m,4H), 3.00 (m,2H), 3.15 (m,1H), 3.20 (m,4H), 3.80(dt,2H), 4.50 (d,2H), 7.20 (dt,1H), 7.60(dd,1H), 7.95 (dd,1H) m.p.156°-160° C. as oxalate 1/3 hydrate thereof.

The following compounds can be prepared in a similar manner as theabove.

EXAMPLE 87

6-formyl-3-isobutyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine oxalate 1/4hydrate, m.p. 165°-167° C.

EXAMPLE 88

6-formyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine hydrochloride 1/2hydrate, m.p. 220° C. (decomposition).

EXAMPLE 89

3-ethyl-6-formyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine oxalate 1/4hydrate, m.p. 188°-190° C.

EXAMPLE 90

6-acetyl-3-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine oxalate 1/3hydrate, m.p. 210°-212° C.

EXAMPLE 91

6-acetyl-3-ethyl-2-(2-(4-(4-fluoro-2-methoxybenzoyl)piperidin-1-yl)ethyl)4,5,6,7-tetrahydrothieno2,3-c!pyridine oxalate, m.p. 134°-136° C.

EXAMPLE 92

6-acetyl-2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propionyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine hydrochloride, m.p. 215° C. (decomposition).

EXAMPLE 93

6-acetyl-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine oxalate 1/4hydrate, m.p. 186°-188° C.

EXAMPLE 94

6-acetyl-2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine oxalate, m.p. 150°-152° C.

EXAMPLE 95

6-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)acetyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine, m.p. 141°-144° C.

EXAMPLE 96

6-acetyl-3-ethyl-2-(2-(4-(2,4-difluorobenzoyl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine 1/2 oxalate 1/2 hydrate, m.p. 128°-131° C.

EXAMPLE 97

6-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-3-propylthieno2,3-c!pyridine fumarate, m.p. 197°-199° C. (decomposition).

EXAMPLE 98

6-acetyl-3-(2-(4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno2,3-c!pyridine 3/2oxalate, m.p. 218° C. (decomposition).

EXAMPLE 99

6-acetyl-3-ethyl-2-(2-(4-(6-fluoro-1H-indazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine oxalate, m.p. 129°-131° C.

EXAMPLE 100

6-acetyl-3-(1-hydroxyethyl)-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine oxalate monohydrate, m.p. 168°-170° C.

EXAMPLE 101

6-acetyl-3-ethyl-2-(2-(4-(2-acetyl-6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine oxalate, m.p. 232° C. (decomposition).

EXAMPLE 102

6-acetyl-3-ethyl-2-(2-(4-(2-ethyl-6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine

¹ H-NMR(CDCl₃)δ:1.10 (t,3H), 1.30 (t,3H), 1.60-2.00 (m,4H), 2.10 (s,3H),2.20-3.40 (m, 14H), 3.50-3.90 (m, 3H), 4.63 (d,2H), 7.00 (dt,1H), 7.36(dd,1H), 7.80 (dd,1H).

EXAMPLE 103

6-acetyl-3-ethyl-2-(2-(4-(2-ethyl-6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine oxalate, m.p. 232° C. (decomposition).

EXAMPLE 104

6-acetyl-3-ethyl-2-(2-(4-(2-methyl-6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 105

6-acetyl-3-ethyl-2-(2-(4-(2-methyl-6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine hydrochloride dihydrate, m.p. 205° C. (decomposition).

EXAMPLE 106

5-acetyl-3-ethyl-2-(2-(4-(2-ethyl-6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno3,2-c!pyridine.

EXAMPLE 107

6-acetyl-3-ethyl-2-(2-(4-(1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine oxalate monohydrate, m.p. 152°-155° C.

EXAMPLE 108

6-acetyl-3-ethyl-2-(2-(4-(4-fluorobenzoyl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 109

6-acetyl-3-ethyl-2-(2-(4-(6-methoxybenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 110

6-acetyl-3-ethyl-2-(2-(4-(6-hydroxybenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 111

5-acetyl-3-ethyl-2-(2-(4-(2-methyl-6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno3,2-c!pyridine.

EXAMPLE 112

5-acetyl-3-ethyl-2-(2-(4-(2-methyl-6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl-4,5,6,7-tetrahydrothieno3,2-c!pyridine.

EXAMPLE-113

5-acetyl-3-ethyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno3,2-c!pyridine.

EXAMPLE 114

5-acetyl-3-ethyl-2-(2-(4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno3,2-c!pyridine.

EXAMPLE 115

5-acetyl-3-ethyl-2-(2-(4-(1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno3,2-c!pyridine.

EXAMPLE 116

5-acetyl-3-ethyl-2-(2-(4-(2-ethyl-6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl-4,5,6,7-tetrahydrothieno3,2-c!pyridine.

EXAMPLE 117

5-acetyl-3-ethyl-2-(2-(4-(4-fluorobenzoyl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno3,2-c!pyridine.

EXAMPLE 118

5-acetyl-3-ethyl-2-(2-(4-(6-methoxybenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno3,2-c!pyridine.

EXAMPLE 119

5-acetyl-3-ethyl-2-(2-(4-(6-hydroxybenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno3,2-c!pyridine.

EXAMPLE 120

5-acetyl-3-ethyl-2-(2-(4-(5-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno3,2-c!pyridine.

EXAMPLE 121

5-acetyl-3-ethyl-2-(2-(4-(5-chloro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno3,2-c!pyridine.

EXAMPLE 122

5-acetyl-3-ethyl-2-(2-(4-(benzo(b)furan-2-yl)piperidin-1-yl)ethyl-4,5,6,7-tetrahydrothieno3,2-c!pyridine.

EXAMPLE 123

5-acetyl-3-ethyl-2-(2-(4-(benzo(b)thiophen-2-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno3,2-c!pyridine.

EXAMPLE 124

5-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-2-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno3,2-c!pyridine hydrochloride, m.p. 218° C. (decomposition).

EXAMPLE 125

5-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)thiophen-2-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno3,2-c!pyridine.

EXAMPLE 126

5-acetyl-3-ethyl-2-(2-(4-(7-bromo-5-methoxybenzo(b)furan-2-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno3,2-c!pyridine.

EXAMPLE 127

6-acetyl-3-ethyl-2-(2-(4-(benzo(b)furan-2-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 128

6-acetyl-3-ethyl-2-(2-(4-(benzo(b)thiophen-2-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 129

6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-2-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 130

6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)thiophen-2-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 131

6-acetyl-3-ethyl-2-(2-(4-(7-bromo-5-methoxybenzo(b)furan-2-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 132

6-acetyl-3-ethyl-2-(2-(4-(6,7-difluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 133

6-acetyl-3-ethyl-2-(2-(4-(5,6-difluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 134

6-acetyl-3-ethyl-2-(2-(4-(6-methyl-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 135

6-acetyl-3-ethyl-2-(2-(4-(6-hydroxy-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 136

6-acetyl-3-ethyl-2-(2-(4-(6,7-dihydroxy-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 137

6-acetyl-3-ethyl-2-(2-(4-(5,6-dihydroxy-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 138

N-ethyl-3-ethyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine-6-carboxamide oxalate 1/2hydrate, m.p. 159°-162° C.

EXAMPLE 139

6-acetyl-3-ethyl-2-(2-(4-(6-fluoro-1,1-dioxobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine hydrochloride dihydrate, m.p. 240° C. (decomposition).

EXAMPLE 140

3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine dihydrochloride 1/4hydrate, m.p. 240°-243° C.

EXAMPLE 141

6-acetyl-3-ethyl-2-(2-(4-(6-methoxy-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 142

3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 143

3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-4-methylthieno3,2-b!azepin-5-one.

EXAMPLE 144

3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-8H-thieno2,3-c!azepin-8-one.

EXAMPLE 145

A mixture of 5.0 g of6-acetyl-2-(2-chloroethyl)-3-ethyl-4,5,6,7-tetrahydrothieno2,3-c!pyridine, 4.9 g of 4-(5-methylbenzo(b)furan-3-yl)piperidinehydrochloride, 2.5 g of potassium carbonate, 3.0 g of potassium iodide,30 ml of dimethylformamide and 30 ml of toluene was stirred at 70° C.for 7 hours and then poured into water. The toluene layer was washedwith water, dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by column chromatography on a silica gel and thendissolved into ethanol to make a hydrochloride. The resulting crystalswere recrystallized from isopropyl alcohol to give6-acetyl-3-ethyl-2-(2-(4-(5-methylbenzo(b)-furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine hydrochloride, m.p. 222°-225° C.

EXAMPLE 146

A mixture of 0.9 g of6-acetyl-2-(2-chloroethyl)-3-ethyl-4,5,6,7-tetrahydrothieno2,3-c!pyridine, 1.0 g of 4-(4,6-dichlorobenzo(b)furan-3-yl)piperidinehydrochloride, 0.5 g of potassium carbonate, 0.5 g of potassium iodide,25 ml of dimethylformamide and 25 ml of toluene was stirred at 80° C.for 6 hours and then poured into water. The toluene layer was washedwith water, dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by column chromatography on a silica gel and thendissolved into ethanol to make a hydrochloride. The resulting crystalswere recrystallized from isopropyl alcohol to give6-acetyl-2-(2-(4-(4,6-dichlorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-3-ethyl-4,5,6,7-tetrahydrothieno2,3-c!pyridine hydrochloride, m.p. 260° C. (decomposition).

EXAMPLE 147

A mixture of 2.0 g of 2-(2-chloroethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one, 2.2 g of 4-(6-fluorobenzo(b)furan-3-yl)piperidinehydrochloride, 2.6 g of potassium carbonate, 1.44 g of potassium iodide,20 ml of dimethylformamide and 20 ml of toluene was stirred at 80° C.for 8 hours and then poured into water. The toluene layer was washedwith water, dried over anhydrous magnesium sulfate and concentrated. Theresidue was recrystallized from ethyl acetate to give2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one, m.p. 176°-178° C.

EXAMPLE 148

A mixture of 2.0 g of 2-(2-chloroethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one, 2.1 g of 4-(5-methylbenzo(b)furan-3-yl)piperidinehydrochloride, 2.6 g of potassium carbonate, 1.5 g of potassium iodide,20 ml of dimethylformamide and 20 ml of toluene was stirred at 80° C.for 8 hours and then poured into water. The toluene layer was washedwith water, dried over anhydrous magnesium sulfate and concentrated. Theresidue was recrystallized from ethyl acetate to give2-(2-(4-(5-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one, m.p. 156°-158° C.

EXAMPLE 149

6-acetyl-3-ethyl-2-(2-(4-(6-fluoro-1,1-dioxobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine hydrochloride dihydrate, m.p. 240° C. (decomposition).

EXAMPLE 150

3-ethyl-2-(2-(4-(6-fluoro-1,2-benzoisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine-6-carboxylic acid ethyl amide oxalate 1/2 hydrate, m.p.159°-162° C.

EXAMPLE 151

3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine dihydrochloride 1/4 hydrate, m.p. 240°-243° C.

EXAMPLE 152

6-acetyl-3-ethyl-2-(2-(4-(6-fluoro-2-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine hydrochloride dihydrate, m.p. 205° C. (decomposition).

EXAMPLE 153

6-acetyl-3-ethyl-2-(2-(4-(1,2-benzoisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine oxalate monohydrate, m.p. 152°-155° C.

EXAMPLE 154

3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one, m.p. 160°-162° C.

EXAMPLE 155

6-acetyl-3-ethyl-2-(2-(4-(5-chlorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine hydrochloride dihydrate, m.p. 209°-211° C.(decomposition).

EXAMPLE 156

5-acetyl-3-ethyl-2-(2-(4-(5-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno3,2-c!pyridine oxalate 1/2 hydrate, m.p. 148°-151° C.

EXAMPLE 157

6-acetyl-3-ethyl-2-(2-(4-(5-methoxybenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine oxalate 1/2 hydrate, m.p. 109°-112° C.

EXAMPLE 158

5-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno3,2-c!pyridine hydrochloride, m.p. 218° C. (decomposition).

EXAMPLE 159

6-acetyl-3-ethyl-2-(2-(4-(5-bromobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine oxalate, m.p. 124°-126° C.

EXAMPLE 160

6-acetyl-3-ethyl-2-(2-(4-(5,6-dimethylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine hydrochloride 1/4 hydrate, m.p. 210 C. (decomposition).

EXAMPLE 161

6-acetyl-3-ethyl-2-(2-(4-(bis(4-fluorophenyl)methylene)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine oxalate, m.p. 212°-213° C.

EXAMPLE 162

6-acetyl-3-ethyl-2-(2-(4-(4-hydroxy-2,6-dimethylbenzoyl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine oxalate 1/2 hydrate, m.p. 198°-200° C.

EXAMPLE 163

6-acetyl-3-ethyl-2-(2-(4-(5-chloro-6-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno3,2-c!pyridine hydrochloride 1/2 hydrate, m.p. 230° C. or above(decomposition).

EXAMPLE 164

6-acetyl-3-ethyl-2-(2-(4-(5-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine hydrochloride 1/4 hydrate, m.p. 200° C. (decomposition).

EXAMPLE 165

3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-5,6,7,8-tetrahydrothieno3,2-c!azepin-4-one hydrochloride, m.p. 260° C. or above (decomposition).

EXAMPLE 166

7-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-8H-thieno2,3-c!azepine hydrochloride monohydrate, m.p. 201°-203° C.

EXAMPLE 167

7-acetyl-3-ethyl-2-(2-(4-(5-chloro-6-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-8H-thieno2,3-c!azepine hydrochloride 1/2 hydrate, m.p. 203°-205° C.

EXAMPLE 168

6-acetyl-3-ethyl-2-(2-(4-(5-methoxybenzo(b)furan-2-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine hydrochloride monohydrate, m.p. 215°-218° C.

EXAMPLE 169

6-acetyl-3-ethyl-2-(4-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine hydrochloride 3/2 hydrate

¹ H-NMR (CDCl₃): 1.20-1.40 (m, 3H), 2.05-2.50 (m, 6H), 2.50-3.18 (m,13H), 3.64-3.92 (m, 5H), 4.60-4.83 (m, 2H), 7.05 (dd, 1H), 7.19 (d, 1H),7.48 (s, 1H), 7.65-7.80 (b, 1H).

EXAMPLE 170

3,6-diacetyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine hydrochloride, m.p. 233°-235° C. (decomposition).

EXAMPLE 171

6-acetyl-3-(1-hydroxyethyl)-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine oxalate, m.p. 193°-196° C.

EXAMPLE 172

6-acetyl-3-ethyl-2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine hydrochloride, m.p. 255° C. or above (decomposition).

EXAMPLE 173

6-acetyl-3-ethyl-2-(2-(4-(5-chloro-2-hydroxybenzoyl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine oxalate monohydrate, m.p. 172°-175° C.

EXAMPLE 174

6-acetyl-3-ethyl-2-(2-(4-(7-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine hydrochloride, m.p. 229°-231° C.

EXAMPLE 175

6-acetyl-3-ethyl-2-(2-(4-(5,7-dimethylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine hydrochloride, m.p. 242°-245° C.

EXAMPLE 176

6-acetyl-3-ethyl-4,5,6,7-tetrahydro-2-(2-(4-(4,6-dimethylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)thieno2,3-c!pyridine hydrochloride 1/4 hydrate, m.p. 230° C. or above.

EXAMPLE 177

6-acetyl-3-ethyl-4,5,6,7-tetrahydro-2-(2-(4-(2-hydroxy-5-methylbenzoyl)piperidin-1-yl)ethyl)thieno2,3-c!pyridine fumarate 1/2 hydrate, m.p. 218°-220° C. (decomposition).

EXAMPLE 178

2-(2-(4-(7-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one, m.p. 188°-190° C.

EXAMPLE 179

2-(2-(4-(benzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 180

2-(2-(4-(4-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 181

2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 182

2-(2-(4-(4-methylbenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 183

2-(2-(4-(5-methylbenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 184

2-(2-(4-(6-methylbenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 185

2-(2-(4-(7-methylbenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 186

2-(2-(4-(4-fluorobenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 187

2-(2-(4-(5-fluorobenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 188

2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 189

2-(2-(4-(7-fluorobenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 190

2-(2-(4-(4-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 191

2-(2-(4-(5-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 192

2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 193

2-(2-(4-(7-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 194

2-(2-(4-(4-fluorobenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 195

2-(2-(4-(5-fluorobenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 196

2-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 197

2-(2-(4-(7-fluorobenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 198

2-(2-(4-(4-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 199

2-(2-(4-(5-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 200

2-(2-(4-(6-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 201

2-(2-(4-(7-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one.

EXAMPLE 202

6-acetyl-3-ethyl-2-(2-(4-(benzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 203

6-acetyl-3-ethyl-2-(2-(4-(4-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 204

6-acetyl-3-ethyl-2-(2-(4-(4-methylbenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 205

6-acetyl-3-ethyl-2-(2-(4-(5-methylbenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 206

6-acetyl-3-ethyl-2-(2-(4-(6-methylbenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 207

6-acetyl-3-ethyl-2-(2-(4-(7-methylbenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 208

6-acetyl-3-ethyl-2-(2-(4-(4-fluorobenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 209

6-acetyl-3-ethyl-2-(2-(4-(5-fluorobenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 210

6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 211

6-acetyl-3-ethyl-2-(2-(4-(7-fluorobenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 212

6-acetyl-3-ethyl-2-(2-(4-(4-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 213

6-acetyl-3-ethyl-2-(2-(4-(5-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 214

6-acetyl-3-ethyl-2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 215

6-acetyl-3-ethyl-2-(2-(4-(7-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 216

6-acetyl-3-ethyl-2-(2-(4-(4-fluorobenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 217

6-acetyl-3-ethyl-2-(2-(4-(5-fluorobenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 218

6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 219

6-acetyl-3-ethyl-2-(2-(4-(7-fluorobenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 220

6-acetyl-3-ethyl-2-(2-(4-(4-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 221

6-acetyl-3-ethyl-2-(2-(4-(5-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 222

6-acetyl-3-ethyl-2-(2-(4-(6-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 223

6-acetyl-3-ethyl-2-(2-(4-(7-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine.

EXAMPLE 224

2-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-8H-thieno2,3-c!azepin-8-one.

EXAMPLE 225

2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-8H-thieno2,3-c!azepin-8-one.

EXAMPLE 226

2-(2-(4-(5-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-8H-thieno2,3-c!azepin-8-one.

EXAMPLE 227

2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-8H-thieno2,3-c!azepin-8-one.

Formulation Example 1

Tablets containing 10 mg of a compound of the formula (I) are preparedin accordance with the following formulation:

    ______________________________________                                        Compound of formula (I)                                                                         10.0 mg                                                     Lactose           58.5 mg                                                     Corn starch       25.0 mg                                                     Crystalline cellulose                                                                           20.0 mg                                                     Polyvinylpyrrolidone K-30                                                                        2.0 mg                                                     Talc               4.0 mg                                                     Magnesium stearate                                                                               0.5 mg                                                                       120.0 mg                                                    ______________________________________                                    

The compound of the formula (I) is pulverized by an atomizer into finepowders below 10 μ in average particle diameter, which are admixed withlactose, corn starch and crystalline cellulose sufficiently in akneading machine, and further kneaded with polyvinylpyrrolidone paste.The kneaded mixture is passed through a sieve of 200 mesh, dried at 50°C. and passed through a sieve of 24 mesh. Talc and magnesium stearateare mixed therewith and the mixture is compressed into 120.0 mg tabletswith a punch of 8 mm in diameter. These tablets are, if desired,subjected to sugar-coating or film-coating.

While the present invention has been adequately and sufficientlydescribed in the foregoing specification including examples, thedescription can be changed or modified within the spirit and scope ofthis invention.

What is claimed is:
 1. A condensed thiophene compound represented by thefollowing formula (I) or a pharmaceutically acceptable salt thereof:##STR44## wherein the ring S is selected from the group consisting ofthe following fused thiophenes: ##STR45## wherein R¹ represents ahydrogen atom, a halogen atom, an alkyl group, an acyl group or ahydroxyalkyl group;R² represents a hydrogen atom, an alkyl group, anacyl group, a carbamoyl group, a substituted carbamoyl group, an arylgroup or an arylalkyl group; G represents a --CH₂ -- group, a--CH(OR³)-- group, a --CO-- group or a --S(O)_(t) -- group; wherein R³represents a hydrogen atom, an alkyl group or an acyl group and t is 0,1, or 2; Q represents a straight alkylene group or a branched chainalkylene group; T represents a tertiary amino group; D represents a--CH₂ group or a --S(O)_(u) -- group; wherein u is 0, 1 or 2; either (i)A is absent and B represents a carbonyl group or a thiocarbonyl group,or (ii) both A and B are absent; when A is absent and B is a carbonylgroup or a thiocarbonyl group, m is 0 and n is 0, 1 or 2; when both Aand B are absent, m is 0 and n is 0 or an integer of 1 to
 4. 2. Thecompound of claim 1 selected from the group consistingof:2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one,3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one, or a pharmaceutically acceptable salt thereof. 3.The compound of claim 1 selected from the group consistingof:2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one,2-(2-(4-(5-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one,2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one,2-(2-(4-(4-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one,2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one,2-(2-(4-(6-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one,2-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno3,2-b!azepin-5-one,2-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-8H-thieno2,3-c!azepin-8-one,2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-8H-thieon2,3 -c!azepin-8 -one,2-(2-(4-(5-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-8H-thieno2,3-c!azepin-8-one,2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-8H-thieno2,3-c!azepin-8-one or a pharmaceutically acceptable salt thereof.
 4. Acondensed thiophene compound of the formula: ##STR46## wherein X ishydroxyl, halogen, methanesulfonyloxy or p-toluenesulfonyloxy, and othersymbols are as defined in claim
 1. 5. A pharmaceutical compositioncomprising a compound of claim 1 and pharmaceutical additives.
 6. Anantipsychotic drug containing a compound of claim 1 as an effectiveingredient.
 7. The compound of claim 1 or a pharmaceutically acceptablesalt thereof, wherein T is a tertiary amino of -N(Rb)(Rc), wherein Rband Rc are the same or different and each is an alkyl group, or Rb andRc together with the adjacent nitrogen atom form a cyclic amino grouprepresented by the following formulae: ##STR47## wherein q is an integerof 1 to 4; Z is methylene or N-R⁵, wherein R⁵ is selected from the groupconsisting of an aryl group, a diarylalkyl group, a heteroaryl group anda heteroarylalkyl group; V is selected from the group consisting of ahydrogen atom, a hydroxyl group, a heteroaryl group, a heteroarylalkylgroup and a bisarylmethylene group and the number of V is 1 to 4; thecyclic amino group of formula (1) may contain a carbonyl group in thecycle and may be condensed with an aryl group or a heteroaryl group; andAm of formula (2) may contain an amido bond in the cycle and may containan oxygen atom, a sulfur atom, a carbonyl group and/or N-R⁶ in the ring,wherein R⁶ is a hydrogen atom, an alkyl group or a phenyl group.